TYPE Review

PUBLISHED 02 October 2023

DOI 10.3389/fimmu.2023.1260592

Effects of inflammation on
OPEN ACCESS myopia: evidence and
EDITED BY
Kun Xiong,
Central South University, China
potential mechanisms
REVIEWED BY
Myriam Chimen, Ran Xu 1,2†, Jing Zheng 1,2†, Longqian Liu 1,2 and Wenqiu Zhang 1,2*
University of Birmingham, United Kingdom
Romania Stilo, Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China,
1

University of Sannio, Italy 2

Department of Optometry and Visual Science, West China Hospital, Sichuan University,
Chengdu, China
*CORRESPONDENCE
Wenqiu Zhang
zhangwenqiu2022@163.com
†
These authors have contributed
equally to this work and share As the most common type of refractive error, myopia has become one of the
first authorship leading causes of visual impairment. With the increasing prevalence of myopia,
RECEIVED 18 July 2023 there is a growing need to better understand the factors involved in its
ACCEPTED 19 September 2023 development. Inflammation, one of the most fundamental pathophysiological
PUBLISHED 02 October 2023
processes in humans, is a rapid response triggered by harmful stimuli and
CITATION conditions. Although controlled inflammatory responses are necessary, over-
Xu R, Zheng J, Liu L and Zhang W (2023)
Effects of inflammation on myopia: activated inflammation is the common soil for many diseases. The impact of
evidence and potential mechanisms. inflammation on myopia has received rising attention in recent years. Elevated
Front. Immunol. 14:1260592.
inflammation may contribute to myopia progression either directly or indirectly
doi: 10.3389/fimmu.2023.1260592
by inducing scleral remodeling, and myopia development may also increase
COPYRIGHT
© 2023 Xu, Zheng, Liu and Zhang. This is an ocular inflammation. This article provides a comprehensive review of the
open-access article distributed under the interplay between inflammation and myopia and the potential biological
terms of the Creative Commons Attribution
mechanisms, which may present new targets for understanding the pathology
License (CC BY). The use, distribution or
reproduction in other forums is permitted, of myopia and developing myopia therapies.
provided the original author(s) and the
copyright owner(s) are credited and that
KEYWORDS
the original publication in this journal is
cited, in accordance with accepted myopia, inflammation, anti-inflammatory drugs, immune diseases, scleral remodeling
academic practice. No use, distribution or
reproduction is permitted which does not
comply with these terms.

1 Introduction
When ocular accommodation is relaxed, light entering the eye from the external
environment parallel to the optical axis is focused in front of the retina, which is called
myopia. During the past 30 years, the myopia population has increased rapidly worldwide,
especially in East and Southeast Asia (1, 2), with the prevalence of myopia among 16-18-
year-olds even reaching 84.8% in China (3). It has been projected that by 2050, half of the
total global population will be myopic (4).Uncorrected refractive error and pathological
myopia have become major causes of visual impairment and even blindness (5, 6).
Therefore, it is particularly important to prevent or delay myopia onset.
A series of signaling pathways, including dopamine (7), retinoic acid (8), Wnt/b-
catenin (9), transforming growth factor-b (TGF-b) (10), and hypoxia-inducible factor-1
alpha (HIF-1a) (11) signaling pathways, have been confirmed to be associated with the
development of myopia; however, the exact pathogenesis of myopia remains unclear since
myopia is regulated by both genetic and environmental factors (12).

Frontiers in Immunology 01 frontiersin.org

Xu et al. 10.3389/fimmu.2023.1260592

Inflammation is an adaptive response of the body to harmful lymphocytes were found during the progression of myopia (20).
stimuli and is beneficial under controlled conditions (13). As one of As indicators of systemic inflammatory properties (21), significantly
the few organs in the body with immune privilege, the eye has higher neutrophil-to-lymphocyte ratios and platelet-to-lymphocyte
unique immunological properties. In general, the ocular ratios in the peripheral blood of patients with high myopia (22, 23)
microenvironment is both immunosuppressive and anti- also implied higher inflammation and dysregulation of serum
inflammatory (14). Under physiological conditions, various immune cells in high myopia population than in normal subjects.
endothelial cells, immune cells (such as microglia, neutrophils, Significant elevations in high-sensitivity C-reactive protein and the
monocytes, macrophages, natural killer cells, etc.) and retinal complement profile in the peripheral blood of patients with
neuronal cells inhibit the activity of effector T cells through the pathological myopia (24) suggested the presence of systemic
release of immunosuppressive factors, promote the formation and immune microinflammation in pathological myopia. In addition,
maintenance of ocular immune privilege and prevent ocular Dai et al (25) elaborated the relevance of oxidative stress,
excessive inflammation (15). Whereas when the eye is subjected inflammation and metabolic changes in high myopia in a study of
to sustained stimulation of damage-associated molecular patterns, human serum metabolomics.
local chronic inflammation mediated by innate immune cells However, such studies have not demonstrated a correlation
develops (16), ultimately leading to destructive tissue remodeling between systemic inflammatory levels and the eye. Besides, they
and loss of visual function through a series of cascade reactions. It might not exclude mixing effects of underlying systemic
has been shown that a low-grade chronic inflammatory response in inflammatory disease.
the eye is associated with the decreased function of retinal
pigment epithelial (RPE), breach of the blood-retinal barrier,
neovascularization and choroidal macrophages recruitment (17). 2.2 Inflammatory status in the ocular
Although inflammation has been identified in relation to many microenvironment of myopia
ocular diseases, the association between it and myopia has not been
confirmed. Recently, researchers have turned their attention to this Current studies tend to consider that the visual mechanisms
area, offering new insights into the specific mechanisms of myopia. regulating refractive development are located primarily in the retina
Inflammatory cytokines activated by mitogen-activated protein (26). Hence, the formation of myopia is considered as a localized
kinase (MAPK), nuclear factor kappa B (NF-kB) and other stimulatory process, and the correlation between myopia and
signaling pathways transmit from the retina to the sclera (18), inflammation of the ocular environment has received more
then directly or indirectly promote myopia. attention than systemic status.
This article reviews the evidence and potential mechanisms Several studies (27–30) have shown that compared to non-
linking inflammation and myopia, and describes the specific myopic eyes, myopic eyes have higher levels of inflammatory
association between myopia and inflammatory or immune cytokines in the aqueous humor or vitreous. The levels of
diseases. In addition, it discusses the potential of anti- interleukin (IL)-6 and metalloproteinase-2 (MMP-2) in aqueous
inflammatory products in the treatment of myopia. humor were positively correlated with the ocular axial length (AL),
and they were also significantly higher in highly myopic eyes than in
control eyes (27). The expression of monocyte chemoattractant
2 Clinical evidence linking protein-1 (MCP-1) in the aqueous humor was significantly higher
inflammation and myopia in highly myopic cataract patients than in age-related cataract
patients, whereas the expression of IL-1 receptor antagonists was
Increasing clinical evidence has shown that the higher significantly lower (28). In addition, the expression of inflammatory
inflammatory status in circulation system or within the eye cytokines, such as interferon gamma (IFN-g), IL-6, interferon-
indicates the severity of myopia and that inflammation may inducible protein 10, eotaxin, MCP-1, macrophage inflammatory
function in the pathogenesis of myopia. protein-1a (MIP-1a), and MIP-1b, was also elevated in the vitreous
of patients with high myopia (29) as well as in highly myopic eyes
with macular holes (MHs) (30). Raised MIP originating from
2.1 Systemic inflammatory status macrophages, dendritic cells and lymphocytes implies that
and myopia immune cells participate in myopia formation.
Studies of bioinformatics analysis likewise confirmed that
Recent studies have found that the systemic immune system is interactions of complement activation, immunity and
involved in myopia. Elevated certain systemic markers suggesting inflammation, and extracellular matrix remodeling may play a
inflammation and imbalances in circulating immune cells in role in the pathogenesis of myopia, especially pathologic myopia
patients with high myopia or pathological myopia indicated that (30–32). Differentially expressed miRNAs in vitreous revealed that
myopic patients might have a systemic hypo-inflammatory status. several signaling pathways, such as the MAPK, phosphatidylinositol
Data from a large cross-sectional study (19) in Korea showed 3-kinase (PI3K)/protein kinase B (AKT), T-cell receptor and
that higher white blood cell counts were significantly associated chemokine signaling pathways associated with inflammation,
with increased myopia prevalence. Meanwhile, elevated circulating were enriched in highly myopic MH eyes (30). Imbalance of the
neutrophils as well as decreased monocytes, eosinophils, and MAPK signaling pathway may also be one of the key steps of lens

Frontiers in Immunology 02 frontiersin.org

Xu et al. 10.3389/fimmu.2023.1260592

alteration in highly myopic eyes (31). Analysis of gene expression other studies (36, 37) likewise observed that inflammation-related
profiles in the cornea showed that immune-related pathways were factors increased in the FDM eye of hamsters with myopia
significantly enriched in myopia. Meanwhile, infiltrating immune progression and that the application of pro-inflammatory agents
cell analysis of the myopic cornea revealed significant enrichment of could also promote the expression of these factors in RPE cells in
B cells, CD4+ memory T cells, CD8+ central memory T cells, T vitro. RPE cells play an important role in myopigenesis, which
helper 2 (Th2) cells, regulatory T cells (Tregs), etc. whereas CD8+ T can recognize key signaling molecules and influence ion and
cells, CD4+ T central memory cells and T helper 1 (Th1) cells were fluid transport to transmit growth-regulating signals from retina
reduced (33). to choroid/sclera (44). Similar experimental results were
The elevated inflammatory cytokines prove the presence of demonstrated in tree shrews undergoing 7/14-day FDM (39).
higher-than-normal ocular inflammatory status in myopic eyes, Since the main innate inflammatory cell population that has
suggesting that the continuous subclinical inflammation within the been described in ocular inflammation is macrophages (16), the
eye may lead to myopia progression. However, there was an investigators discussed the link between macrophages and myopia.
inconsistent report on the association between myopia and It was found that in addition to scleral fibroblasts, monocyte-
inflammation. Zhu et al (34) showed no significant link between derived scleral macrophages induced by scleral C-C motif
AL and inflammatory cytokines (IL-1b, IL-6 and tumor necrosis chemokine ligand-2 (CCL2) were one of the sources of MMP-2 in
factor-alpha (TNF-a)) in aqueous humor in cataract patients the eye (45). Secreted MMP-2 hydrolyzed collagen fibrils and
with AL ranging from 22.6-31.5 mm. The conflicting results recollects monocytes and neutrophils (46). In cases of negative
could be due to differences in sample size, testing instruments, lens-induced myopia, macrophage-like cells were observed to
and inclusion criteria. directly phagocytose collagen fibrils as well as fibroblasts in sclera
It should be noted that current clinical evidence cannot fully (47). This indicates that macrophages contribute to the
elucidate the correlation between myopia and inflammation. First, development of myopia.
the results are not representative, because the aqueous humor and In addition, RNA sequencing results also demonstrated the
vitreous samples involved in these studies could only be obtained activation of inflammation-related signaling pathways in
surgically. The level of inflammation in myopic patients who do not experimental myopic eyes. Single-cell RNA sequencing showed
require surgery is not known. Second, the characteristics of subjects sustained expression of MAPK, and PI3K/AKT signaling
in myopia stabilization and the design of cross-sectional studies pathways in scleral fibroblasts from mice experiencing 4 weeks of
limit the determination of the causal relationship between myopia FDM (40). RNA-seq analysis of retinas from guinea pigs
and inflammation. Besides, pathologic myopia itself has been shown undergoing 15 weeks of FDM (41) suggested that inflammatory
to be related to the autoimmune and inflammatory systems (35). pathways such as inflammatory mediator regulation of Tryptophan
Therefore, the basic experiments are needed to provide supporting channels and IL-17 signaling pathway played crucial roles in of
evidence for previous clinical contribution. myopia-induced retinal degeneration.
The complement system is an important component of innate
immunity (48). The level of C5b-9 was significantly elevated in the
3 Inflammation in experimental posterior sclera of guinea pigs (42) with negative lens-induced
myopic model myopia (LIM), with increased C1q and C3 protein expression.
Transcription and activation of the complement system were
Studies have shown that expression of ocular inflammatory also present during the induction of myopia and hyperopia in
cytokines increases with the development of myopia in different chicks (43).Activation of the complement system may trigger
species of experimental myopia, including hamsters (18, 36–38), inflammatory responses in some ocular diseases such as primary
tree shrews (39), mice (40), guinea pigs (41, 42), and chicks (43), angle closure glaucoma (49), and these inspire us that complement
and that increased ocular inflammatory status promotes the may function in myopia through inflammation.
development of myopia. In contrast to previous studies (18), Jody et al (50) argued that
The inflammatory cytokines were activated and transmitted the recovery from FDM or myopic defocus affecting the expression
from retinal to scleral during myopia induction. The inflammation- of those proinflammatory cytokine, despite affirming that IL-6 in
associated transcription factors c-Fos and NF-kB and the the choroid plays an important role in the retina-sclera signaling
inflammatory cytokines IL-6, TNF-a, IL-1b, TGF-b and MMP-2 cascade. They found that IL-6 expression was increased in the chick
were upregulated, while the anti-inflammatory cytokine IL-10 was choroid during recovery from FDM or during the application of a
decreased in myopic eyes of Syrian hamsters induced by form- +15D lens and was upregulated in myopic eyes treated with
deprivation myopia (FDM) (18), suggesting that pathways atropine. However, unlike the previous experimental design, this
associated with inflammation-induced myopia may include the study focused on IL-6 in the choroid.
MAPK and NF-kB pathways. Meanwhile, the immunosuppressive In conclusion, most studies agree that the development
agent cyclosporine A applied to the eye delayed myopia of myopia is accompanied by increased levels of ocular
progression, while inflammatory stimulators peptidoglycan and inflammation, and that increased inflammation in the eye
lipopolysaccharide promoted myopia progression (18). Several predisposes to myopia.

Frontiers in Immunology 03 frontiersin.org

Xu et al. 10.3389/fimmu.2023.1260592

4 Correlation between myopia and inflammatory cytokines such as IL-1 and TNF-a in uveitis (58)
and scleritis (59) may lead to the dysregulation of MMPs and tissue
inflammatory or immune diseases inhibitors of metalloproteinases (TIMPs), resulting in degradation of
scleral collagen, and the reduction in perfusion of ocular vasculature
Several studies have noted a link between inflammatory or
caused by inflammation (60, 61) may likewise lead to scleral ischemia,
immune diseases and myopia, with patients who exist abnormal
hypoxia and remodeling.
inflammatory or immune status having a higher prevalence of
myopia than normal individuals. These diseases may be a risk
factor for myopia, although the correlation has not been
4.2 Systemic diseases
fully evaluated.

The relationship between myopia and systemic immune or

inflammatory diseases has gradually attracted researchers’
4.1 Ocular diseases attention. Diseases such as Vogt−Koyanagi−Harada (VKH)
disease, juvenile idiopathic arthritis (JIA), systemic lupus
It has been reported that ocular inflammatory diseases, erythematosus (SLE), and Kawasaki disease (KD) were reported
including allergic conjunctivitis (AC) (51, 52), scleritis (53–55), to be associated with myopia.
and uveitis (18, 56, 57), may trigger the progression of myopia by VKH disease is a T-cell-mediated systemic autoimmune disease
elevating ocular inflammation. that primarily targets melanocytes (62). A retrospective study (63)
A study by Mimura (51) showed that AC patients who were about refractive changes in VKH patients found that 16% of eyes
positive for specific immunoglobulin E to indoor allergens exhibited showed significant myopic progression and that sunset glow fundus
higher degree of myopia than healthy subjects, linking allergic was more frequent in these patients than in those without myopia
conjunctivitis to myopia for the first time. Subsequently, a case progression. Some patients with chronic VKH also experienced
−control and cohort study (52) showed a significantly higher risk myopia progression and growth of AL (64). JIA is an
and incidence of myopia in patients with AC than in those with autoinflammatory disease, which is a general term covering all
nonallergic conjunctivitis, validating the causal relationship arthritis of unknown origin that develops under the age of 16 years
between AC and myopia. Furthermore, they also demonstrated and lasts for more than 6 weeks (65). A previous study (66) reported
again in Lewis rat model of AC that the presence of AC triggers that the prevalence of myopia was increased in patients with
ocular surface inflammation, activates pro-inflammatory factors, juvenile chronic arthritis compared to their peers and that
leading to scleral remodeling and eye axis growth (52). myopia occurred after the diagnosis of this disease. The results of
The association between scleritis and myopia has mainly been another research (67) also found 42% of 40 JIA patients had
focused on case reports. Fan (53) and Ugurbas (54) reported that in myopia, but the number of myopic patients was not significantly
addition to common ocular pain, scleritis may occur as sudden different between those with and without uveitis. Thus, the elevated
monocular myopia, followed by typical clinical and imaging risk of myopia in patients with JIA may not completely be
findings. During follow-up, 10-30% of patients with necrotizing associated with induced uveitis. The mechanism of their
scleritis may have a visual acuity of 0.1 or worse at some point in induction of myopia is more likely to be through the increased
time (55). Although myopia is not a prevalent symptom of scleritis, inflammatory status of the eye caused by the diseases themselves.
there seems to be an association between them. SLE is a chronic, autoimmune inflammatory connective tissue
Uveitis can cause acute, transient or persistent myopia in disease affecting multiple organ systems. Although myopia is not a
different conditions (56). A retrospective cohort study (18) found common ocular manifestation of SLE, several cases have reported
an increased risk and cumulative incidence of myopia in patients that acute episodes of reversible myopia may be a feature of SLE
with uveitis. Meanwhile, data from research (57) with a 15-year (68–70). A retrospective study (18) likewise showed that patients
follow-up of chorioretinal inflammatory diseases showed that with SLE had a higher risk of myopia and a higher cumulative
myopic refractive changes were present in some inflammatory prevalence of myopia than healthy patients of the same age. Similar
disease, including multifocal choroiditis and panuveitis (mean to scleritis and uveitis, the pathogenesis of myopia due to SLE may
-2.19 D), punctate inner choroidopathy (mean -3.67 D), diffuse lie in uveal effusion and ciliary swelling due to choroidal vasculitis
subretinal fibrosis syndrome (mean -1.25 D), and multiple (71), which subsequently cause lens-induced myopic shift. When
evanescent white dot syndrome (mean -1.25 D). the inflammatory response subsides or is controlled, part of the
The high risk of myopia due to AC may be associated with myopic shift may gradually disappear.
elevated ocular surface inflammation, whereas the cause of myopia in KD is a systemic inflammatory disease of unknown etiology,
patients with scleritis and uveitis is more often thought to be changes where one of its pathogenesis lies in dysregulation of the immune
in lens refractive power and the elongation of AL. Inflammation of system and abnormal T-cell function due to triggering of the
the sclera and uvea may present with uveal effusion, ciliary exudation, inflammatory cascade response (72). A prospective cohort study
swelling, or detachment, leading to relaxation of the suspensory (73) of KD and non-KD children aged 0-6 years in Taiwan found
ligaments and zonular fibers, increasing the refractive power of the that KD was an independent risk factor for myopia regardless of
lens and causing myopic shift (53). In addition, elevated age, sex, and urbanization. And the risk of myopia in KD patients

Frontiers in Immunology 04 frontiersin.org

Xu et al. 10.3389/fimmu.2023.1260592

increased with the growth of age as well as frequency of clinic visits. In terms of molecular mechanisms and signaling pathways,
The incidence of myopia was significantly lower in KD patients myopigenesis may initiate in the retina, pass through the choroid,
treated with intravenous immunoglobulin (IVIG) than in those and finally reach the sclera, inducing scleral remodeling (79).
treated with aspirin alone (74). Although both aspirin and During this process, the retina-sclera signaling cascade promotes
immunoglobulin have anti-inflammatory effects, the anti- the increase of MMP-2, the degradation of TGF-b, and scleral
inflammatory effect of IVIG appears to be stronger than that of myofibroblast transdifferentiation, resulting in abnormal
aspirin, with patients receiving only aspirin or low IVIG + aspirin extracellular matrix (ECM) metabolism, reduction of collagen
having a significantly longer duration of fever and a significantly type I and glycosaminoglycans (GAGs). Subsequently, the sclera
higher incidence of coronary aneurysms than KD patients receiving undergoes tissue remodeling and thinning of the posterior pole,
high IVIG + aspirin (75). Thus, the lower risk of myopia in patients leading to the formation of axial myopia (80) (Figure 1).
receiving IVIG could be explained from the perspective of reducing Inflammation attracts cytokines, blood cells, growth factors and
the inflammatory response, and the association between myopia so on to the site of infection or injury, then allows tissue remodeling
and inflammatory diseases could also be supported. through protein hydrolytic activity and function or connective
In summary, the evidence described above implied that myopia tissue rebuilding (81). Therefore, given the inflammatory
was related to the inflammatory features of certain diseases. susceptibility of the sclera and the pathophysiological
However, most of these studies were cross-sectional without mechanisms promoted by inflammation, it can be assumed that
showing specific causal relationships, and studies correlating the direct contribution of inflammation to myopia onset may be
refractive error or AL with the severity of inflammation are accomplished through a retina-sclera signaling cascade that induces
lacking. It should be noted that due to restricted physical ability, scleral remodeling.
patients with chronic inflammatory diseases may spend less time TNF-a is a proinflammatory cytokine produced mainly by innate
outdoors or expose to the natural light, and may also experience immune cells or T cells that exerts multiple biological activities by
more time in close proximity or using electronics, all of above are binding and activating two different receptors (82). Ligation of TNF-
risk factors for myopia. In addition, the refractive power of the eye a with TNF receptor 1 leads to the assembly of complex I, which then
depends on the curvature of surface of cornea and lens, refractive activates NF-kB and MAPKs to promote inflammation and tissue
indices of refractive medium and AL (76), all of which are not degeneration (83). Activation of TNF receptor 2 also results in the
clearly related to inflammation. Therefore, there is still insufficient assembly of complex I and activation of downstream signaling
evidence to determine whether inflammation is an independent risk pathways which mainly mediates homeostatic bioactivities (83).
of myopia. Ocular TNF-a is mainly released by microglia and Müller cells,
causing apoptosis of retinal pigment epithelial cells and disrupting the
blood−retinal barrier through activation of the epidermal growth
5 Potential biological mechanisms factor receptor (EGFR)/p38/NF-kB/p62 pathway (84). Additionally,
between inflammation and myopia it can positively stimulate glial proliferation and accelerate the release
of other proinflammatory factors of Müller cells (85).
Overall, the potential biological mechanisms by which As a pleiotropic cytokine that promotes inflammation, IL-1b is
inflammation affects myopia may include the direct induction rarely present in cells of healthy individuals. Its transcription is
of scleral remodeling by inflammatory signaling pathways, induced by TNF-a, IL-18, IL-1a or IL-1b itself through activation
including MAPK and NF-kB, and the indirect effects of the of the NF-kB pathway (86). Mature IL-1b activates TGF-b-
influence of inflammation on retinal and choroidal blood activated kinase 1(TAK1) through a series of signaling pathways,
vasculature, interference with dopamine, modulation by which then initiates the MAPK cascade response and NF-kB
extracellular vesicles (EVs) and regulation of the refractive transcription (87), promoting inflammatory mediator recruitment
index of the lens. such as IL-6, IL-8 and TNF-a and local/systemic inflammatory
responses. Increased ocular IL-1b is capable of triggering an
immediate inflammatory response in the retina, destroying retinal
5.1 Direct contribution of inflammatory capillary endothelial cells, inducing angiogenesis and causing
signaling pathways MAPK and NF-kB to dysregulation of nitric oxide (NO) (88), the expression of which
scleral remodeling was increased during FDM (89).
IL-6 is a cytokine with pro- and anti-inflammatory properties
From an anatomical and pathological point of view, the sclera, in that is activated by innate immune cells during inflammation. The
common with cartilage, tendons, bone, ligaments, dermis, and classical pathway of IL-6 bound to the IL-6 receptor exerts anti-
perivascular muscle tissue, is of dual neural crest and mesodermal inflammatory properties, whereas trans-signaling of IL-6 bound to
tissue origin and maintains the potential to form cartilage throughout the soluble IL-6 receptor acts as a pro-inflammatory mediator (90).
evolution (77). Thus, similarly to articular cartilage, the sclera is often It activates MAPKs and NF-kB through activation of Janus kinase
a target of inflammatory cells in immunoinflammatory diseases (78). (JAK) to mediate downstream responses (91). Trans-signaling of
From this perspective, a correlation between inflammation and IL-6 can lead to oxidative stress, endothelial cell dysfunction,
myopia is possible. inflammation and neovascularization within the human retina

Frontiers in Immunology 05 frontiersin.org

Xu et al. 10.3389/fimmu.2023.1260592

FIGURE 1
The mechanism of scleral remodeling during myopia. This figure illustrates the general mechanism of scleral remodeling in myopia. The retina
recognizes stimuli or visual signals associated with myopia and transmits them to the sclera via the choroid, resulting in elevated MMP-2, reduced
TGF-b, and transdifferentiation of scleral myofibroblasts, which leads to changes in the composition of the scleral stroma, elongation of the posterior
pole of the eye, and finally the development of myopia. Created by figdraw.com.

(92). Dysregulated and persistent production of IL-6 has been phosphorylated IkB kinase (IKK) complex, including catalytic
implicated in the development of various chronic inflammatory subunit IKKa, IKKb and regulatory subunit IKKg (also known as
diseases (93)including inflammatory ocular disease (94). NF-kB essential modulator, NEMO), leads to the ubiquitination and
MMPs are key enzymes involved in ECM remodeling. MMP-2 degradation of IkB. The degraded IkB thereby releases activated NF-
expression preceding myopigenesis can be observed in FDM, kB dimers into the nucleus and subsequently regulates gene
whereas its decline can also directly impede myopia progression transcription (101). There are also interactions existing between the
(95). The expression of MMPs is upregulated at the transcriptional MAPK and NF-kB signaling pathways. Phosphorylation of IkB can
level by many inflammatory cytokines (96). Activated MMPs are be activated by activated protein kinases downstream of MAPK, and
able to regulate the availability and activity of inflammatory similarly, NF-kB can mediate the activation of downstream targets of
mediators such as TNF-a and IL-1b and induce the migration of MAPK on inflammatory cytokines (102). Both pathways function in
inflammatory cells to inflammatory sites by modifying chemotactic ocular surface inflammation, such as dry eye, keratitis, and allergic
agents (97). conjunctivitis, and regulate apoptosis of retinal ganglion cells
MAPK, a kind of evolutionarily highly conserved serine/ (103, 104).
threonine protein kinase, contains several members, including c- Given the considerable overlap in the target genes activated by
Jun NH2-terminal kinase (JNK), p38 MAPK, and extracellular signal- the MAPK and NF-kB signaling pathways, it is hypothesized that
regulated kinase (ERK) (98). Inflammatory cytokines or other stimuli both signaling pathways may be jointly involved in the pathological
trigger signal transduction by sequentially activating MAP kinase process of myopia (Figure 2). Ocular inflammatory diseases or
kinase kinase (MAPKKK), MAP kinase kinase (MAPKK), and abnormal visual stimulus in the retina stimulate the production of
MAPK, and then activate downstream kinases or transcription inflammatory cytokines, such as TNF-a, IL-1b, and IL-6. These
factors to mediate cell proliferation, differentiation, apoptosis, and increased cytokines then activate MAPKKK and IKK through a
inflammatory responses (99). As a transcription factor, NF-kB is a series of signal transduction, and consequently trigger MAPK and
central mediator of proinflammatory gene induction and functions in NF-kB signaling pathways, which initiate downstream signaling
both innate and adaptive immune cells, which can induce the and drive the production of numerous proinflammatory cytokines.
production of downstream molecules such as inflammatory These agents then activate MMP-2 expression in the retina,
cytokines, chemokines, and adhesion molecules, directly targeting followed by the sclera, leading to cleavage of collagen, causing
inflammation (100). In resting status, the majority of NF-kB scleral remodeling as well as the onset of myopia. In this process,
consisting of p50 and p65 heterodimers remains inactive by activated TNF-a and IL-1b also promote the expression of other
bounding to the inhibitory proteins of NF-kB (IkB) in the proinflammatory factors, such as IL-6, IL-8, and MCP-1, while
cytoplasm. Upon receipt of activation signals, the activated and acting again on MAPKKK as well as IkB (101) to regulate both

Frontiers in Immunology 06 frontiersin.org

Xu et al. 10.3389/fimmu.2023.1260592

FIGURE 2
Schematic representation of inflammatory signaling pathways inducing scleral remodeling. After recognizing inflammatory stimuli, increased
inflammatory cytokines such as TNF-a, IL-1b, and IL-6 in the retina activate IKK as well as MAPKKK, initiating NF-kB as well as MAPK signaling
pathways. Both two ultimately trigger the expression of TNF-a, IL-1b, and IL-6, which then activate MMP-2 and subsequently lead to scleral
remodeling and finally the onset of myopia. During this process, the increased MMP-2 produced by progressive myopia re-activates TNF-a, IL-1b,
and IL-6, whose increase act as inflammatory stimulus for the reactivation of both pathways. Created by figdraw.com.

pathways. Meanwhile, the progression of myopia produces more 5.3 Inflammatory interference
MMP-2, promoting further release of inflammatory factors and with dopamine
ultimately creating a malignant cycle.
As an important factor in myopic regulatory pathways, the
protective effect of dopamine on myopia has been well documented
5.2 Impact of inflammation on the retinal (7). Available evidence also suggests that inflammatory cytokines
and choroidal vasculature c an p o t e n t i a l ly a ff e c t m u l t i pl e a s p e c t s o f d op a m i n e
neurotransmission, leading to decreased synthesis, impaired
Increased ocular inflammation may also affect myopia through packaging or release, and increased reuptake of dopamine,
the ocular vasculature. Chronic inflammation activates endothelial ultimately resulting in reduced dopamine signaling in the basal
cells, and endothelial dysfunction leads to reduced vasodilator ganglia (110). Therefore, it can be speculated that increased
function, leukocyte recruitment, decreased NO bioavailability, and inflammatory cytokines in the eye may similarly reduce ocular
increased oxidative stress (105), triggering impaired ocular dopamine by interfering with dopamine synthesis and release in
microvascular circulation and oxygen supply. Since retinal and retina to exacerbate myopia development.
choroidal vascular microcirculation provides oxygen and material
exchange directly to the retina and sclera (106), the impaired ocular
microvascular circulation and increased oxidative stress caused by 5.4 Inflammatory modulation by
inflammation may directly lead to inadequate perfusion and extracellular vesicles
reduced supply of oxygen. The scleral hypoxia causes the
accumulation of HIF-1a, myofibroblast transdifferentiation, and In view of the important role of EVs in intercellular
decreased collagen production, ultimately leading to scleral communication and inflammatory regulation, they may serve as
remodeling and the development of myopia (107). This is an additional bridge between inflammation and myopia. EVs,
consistent with the reduced density and lower blood flow in the including microvesicles, exosomes, and apoptotic bodies (111),
choroidal and retinal microvasculature and reduced oxygen are capable of carrying numerous cytokines, such as IL-6, TNF-a,
saturation in small retinal arteries that occur in myopic eyes (108, CCL2, and TGFb, protecting them from enzymatic degradation and
109). Additionally, with obstruction of blood flow, monocytes delivering them to distant cells (112). All types of immune cell
within the choroidal vessels gradually migrate toward the sclera involved in inflammation can secrete EVs, while EVs are able to
due to increased vascular permeability and subsequently influence the behavior of innate immune cells and cytokine
differentiate into MMP-2 (45), again aggravating myopia. expression by transferring various mediators to modulate the level

Frontiers in Immunology 07 frontiersin.org

Xu et al. 10.3389/fimmu.2023.1260592

of inflammation (113). In pathological states, ocular exosomes treatment of myopia also involves inhibition of muscarinic
could mediate ECM remodeling, retinal inflammation, and blood- acetylcholine receptor activation and consequent inhibition of
retinal barrier dysfunction (114). Lately, researchers found that inflammation-related signaling pathways (18).
exosomes in the aqueous humor of myopic patients contained more Besides, given that artificial exosomes have been shown to be
total RNA compared to control group (115), and key exosomal able to treat ocular inflammatory diseases by inhibiting the
microRNAs, such as miR-143-3p, miR-145-5p and has-miR-518d- infiltration of inflammatory cells (123), reducing the expression of
3p associated with high myopia and pathological myopia were pro-inflammatory cytokines (124), and protecting the structure and
successively identified (115–117), suggesting that exosomes also function of the retina and retinal ganglion cells (125), it is
contribute to the process of myopia. Due to the small particle size reasonable to believe that artificial exosomes may also be a new
and well traversed ability to the blood-retinal barrier (BRB) (118), it target for myopia treatment.
is reasonable to speculate that in systemic inflammatory diseases, Therefore, anti-inflammatory drugs and artificial exosomes may
elevated inflammatory cytokines in the peripheral blood may be become a new option for the treatment of myopia after low-dose
carried by EVs and enter the eye through the BRB, thereby affecting atropine. However, as the relationship and exact mechanism
myopia. Meanwhile, ocular exosomes may induce an exacerbation between inflammation and myopia are not yet defined, the
of ocular inflammatory state through activation of immune cells in efficacy has only been confirmed in animal experiments, and the
the eye, hence participating in the development of myopia. safety, dose, mode of administration, and side effects of these drugs
are still unknown. Further verification is needed to determine
whether anti-inflammatory drugs can actually be used to treat
5.5 Regulation of the refractive index of myopia in humans.
the lens by inflammation

In patients with certain inflammatory or immune diseases, 7 Summary and future

apart from the possible mechanisms described previously,
increased inflammation may also cause reversible or permanent To our knowledge, this is the first review to comprehensively
myopia through uveal effusion or ciliary swelling, which may relax interpret the association between myopia and inflammation. Low-
the suspensory ligament and ciliary muscle, increasing the distance grade inflammation in the body can induce myopia progression,
between the fovea and lens and subsequently increasing the and the prevalence of myopia has been found to be elevated in
refractive index of the lens. patients with inflammatory or immune diseases. The association
between them has also been confirmed in experimental myopia. In
addition, anti-inflammatory drugs and artificial exosomes have
6 Potential of anti-inflammatory drug inhibitory effects on myopia. Specific mechanisms of
to intervene myopia inflammation-induced myopia may include scleral remodeling
caused by dysregulation of the MAPK and NF-kB signaling
The main measures considered to reduce the occurrence of pathways and the effects of inflammation on the ocular
myopia and prevent its progression include public health vasculature, dopamine, the inflammatory modulation by EVs and
interventions, optical measures, and pharmacological treatments. the refractive index of the lens (Figure 3).
Among these, spending more time outdoors can significantly Considering the impact of inflammation on myopia, more
reduce the prevalence of myopia (119); multifocal soft contact frequent ophthalmic screening, more outdoor activities and
lenses, peripheral plus spectacles, multifocal spectacles, and education are needed to prevent myopia in younger patients with
orthokeratology have been shown to slow refractive change and inflammatory or immune diseases, while stronger interventions are
axial elongation (120). For pharmacological measures, the daily needed in those who are already myopic. Additionally, given the
application of low-dose atropine eye drops has been widely used as effectiveness of anti-inflammatory drugs in animal studies, the
medical prophylaxis for myopia progression (121). However, possibility of combining anti-inflammatory products with low
atropine has side effects such as rebound after discontinuation, concentrations of atropine to better control myopic progression
hotophobia or glare, blurred vision (particularly for near vision) could be considered. Furthermore, in adult patients with sudden
and hypersensitivity reactions (120). Finding more drugs for the myopia progression, it is important to be alert for insidious onset of
treatment of myopia based on promising signaling pathways is one endophthalmitis, such as uveitis, posterior pole scleritis,
of the current research hotspots. and choroiditis.
The hypothesis that myopia may be suppressed by the anti- In conclusion, although the association between inflammation
inflammatory effects of drugs is supported by the association and myopia has not been fully assessed, inflammation may be a
between inflammation and myopia. Lactoferrin (122), diacerein potential new target for myopia. As potential regulators of
(36), and resveratrol (37) have been shown to reduce the inflammation, macrophages, microglia, and endothelial cells in
progression of experimental myopia in animals by inhibiting the the eye may be a promising area of research, especially with
expression of inflammatory cytokines related to the MAPK or NF- regard to the precise regulation of immune cells, the timing of
kB signaling pathways in the retina. The mechanism of atropine activation, and cell-cell communication. Meanwhile, investigations

Frontiers in Immunology 08 frontiersin.org

Xu et al. 10.3389/fimmu.2023.1260592

FIGURE 3
Potential mechanisms between inflammation and myopia. Increased inflammation can induce myopia. The over-activated MAPK and NF-kB
signaling pathways activate inflammatory factors and MMP-2 in the retina, followed by transmission to the sclera, leading directly to scleral
remodeling. Chronic inflammation damages the endothelium of ocular vasculature, causing impaired blood circulation and triggering ischemia of
retina and choroid as well as scleral hypoxia. Meanwhile, inflammation also leads to the reduction in retinal dopamine release and the activation of
EVs. In addition, some patients may suffer from uveal effusion or ciliary swelling by inflammation, which ultimately leads to increased refractive
power of lens. Created by figdraw.com.

on the exact causal relationship between inflammation and myopia, Conflict of interest
the molecule signaling pathways in myopia, the therapeutic effects
of artificial exosomes and anti-inflammatory drugs should not The authors declare that the research was conducted in the
be neglected. absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
Author contributions
RX: Writing – original draft. JZ: Writing – original draft. LL:
Publisher’s note
Writing – review & editing. WZ: Writing – review & editing.
All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their affiliated
Funding organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
This work was supported by the National Natural Science claim that may be made by its manufacturer, is not guaranteed or
Foundation of China [Grant Number 81800863]. endorsed by the publisher.

References
1. Morgan IG, French AN, Ashby RS, Guo X, Ding X, He M, et al. The epidemics of 5. Flaxman SR, Bourne RRA, Resnikoff S, Ackland P, Braithwaite T, Cicinelli MV,
myopia: Aetiology and prevention. Prog Retin Eye Res (2018) 62:134–49. doi: 10.1016/ et al. Global causes of blindness and distance vision impairment 1990-2020: a
j.preteyeres.2017.09.004 systematic review and meta-analysis. Lancet Glob Health (2017) 5(12):e1221–34.
2. Sankaridurg P, Tahhan N, Kandel H, Naduvilath T, Zou H, Frick KD, et al. doi: 10.1016/S2214-109X(17)30393-5
IMI impact of myopia. Invest Ophthalmol Vis Sci (2021) 62(5):2. doi: 10.1167/ 6. Saw SM, Matsumura S, Hoang QV. Prevention and management of myopia and myopic
iovs.62.5.2 pathology. Invest Ophthalmol Vis Sci (2019) 60(2):488–99. doi: 10.1167/iovs.18-25221
3. Dong L, Kang YK, Li Y, Wei WB, Jonas JB. Prevalence and time trends of myopia 7. Zhou X, Pardue MT, Iuvone PM, Qu J. Dopamine signaling and myopia
in children and adolescents in China: A systemic review and meta-analysis. Retina development: What are the key challenges. Prog Retin Eye Res (2017) 61:60–71.
(2020) 40(3):399–411. doi: 10.1097/IAE.0000000000002590 doi: 10.1016/j.preteyeres.2017.06.003
4. Holden BA, Fricke TR, Wilson DA, Jong M, Naidoo KS, Sankaridurg P, et al. 8. Yu M, Liu W, Wang B, Dai J. Short wavelength (Blue) light is protective for lens-
Global prevalence of myopia and high myopia and temporal trends from 2000 through induced myopia in Guinea pigs potentially through a retinoic acid-related mechanism.
2050. Ophthalmology (2016) 123(5):1036–42. doi: 10.1016/j.ophtha.2016.01.006 Invest Ophthalmol Visual Sci (2021) 62(1). doi: 10.1167/iovs.62.1.21

Frontiers in Immunology 09 frontiersin.org

Xu et al. 10.3389/fimmu.2023.1260592

9. Liu Z, Xiu Y, Qiu F, Zhu Z, Zong R, Zhou X, et al. Canonical wnt signaling drives 35. Ohno-Matsui K, Wu PC, Yamashiro K, Vutipongsatorn K, Fang Y, Cheung
myopia development and can be pharmacologically modulated. Invest Ophthalmol Vis CMG, et al. IMI pathologic myopia. Invest Ophthalmol Vis Sci (2021) 62(5):5.
Sci (2021) 62(9):21. doi: 10.1167/iovs.62.9.21 doi: 10.1167/iovs.62.5.5
10. Zhu X, Du Y, Li D, Xu J, Wu Q, He W, et al. Aberrant TGF-beta1 signaling 36. Tien PT, Lin CH, Chen CS, Chang CY, Ku H, Gan D, et al. Diacerein inhibits
activation by MAF underlies pathological lens growth in high myopia. Nat Commun myopia progression through lowering inflammation in retinal pigment epithelial cell.
(2021) 12(1):2102. doi: 10.1038/s41467-021-22041-2 Mediators Inflamm (2021) 2021:6660640. doi: 10.1155/2021/6660640
11. Zhao F, Zhang D, Zhou Q, Zhao F, He M, Yang Z, et al. Scleral HIF-1alpha is a 37. Hsu YA, Chen CS, Wang YC, Lin ES, Chang CY, Chen JJ, et al. Anti-
prominent regulatory candidate for genetic and environmental interactions in human inflammatory effects of resveratrol on human retinal pigment cells and a myopia
myopia pathogenesis. EBioMedicine (2020) 57:102878. doi: 10.1016/j.ebiom.2020.102878 animal model. Curr Issues Mol Biol (2021) 43(2):716–27. doi: 10.3390/cimb43020052
12. Wolffsohn JS, Flitcroft DI, Gifford KL, Jong M, Jones L, Klaver CCW, et al. IMI - 38. Wei CC, Lin HJ, Lim YP, Chen CS, Chang CY, Lin CJ, et al. PM2.5 and NOx
myopia control reports overview and introduction. Invest Ophthalmol Vis Sci (2019) 60 exposure promote myopia: clinical evidence and experimental proof. Environ pollut
(3):M1–M19. doi: 10.1167/iovs.18-25980 (2019) 254(Pt B):113031. doi: 10.1016/j.envpol.2019.113031
13. Medzhitov R. Origin and physiological roles of inflammation. Nature (2008) 454 39. Ku H, Chen JJ, Hu M, Tien PT, Lin HJ, Xu G, et al. Myopia development in tree
(7203):428–35. doi: 10.1038/nature07201 shrew is associated with chronic inflammatory reactions. Curr Issues Mol Biol (2022) 44
14. Keino H, Horie S, Sugita S. Immune privilege and eye-derived T-regulatory cells. (9):4303–13. doi: 10.3390/cimb44090296
J Immunol Res (2018) 2018:1679197. doi: 10.1155/2018/1679197 40. Yu J, Mo Y. Gene expression profiles of myopic mouse scleral fibroblasts: a
15. Wang X, Wang T, Lam E, Alvarez D, Sun Y. Ocular vascular diseases: from bioinformatics analysis based on single-cell RNA sequencing. Nan Fang Yi Ke Da Xue
retinal immune privilege to inflammation. Int J Mol Sci (2023) 24(15). doi: 10.3390/ Xue Bao (2021) 41(7):1087–92. doi: 10.12122/j.issn.1673-4254.2021.07.18
ijms241512090 41. Zeng L, Li X, Liu J, Liu H, Xu H, Yang Z. RNA-seq analysis reveals an essential
16. Murakami Y, Ishikawa K, Nakao S, Sonoda KH. Innate immune response in role of the tyrosine metabolic pathway and inflammation in myopia-induced retinal
retinal homeostasis and inflammatory disorders. Prog Retin Eye Res (2020) 74:100778. degeneration in Guinea pigs. Int J Mol Sci (2021) 22(22). doi: 10.3390/ijms222212598
doi: 10.1016/j.preteyeres.2019.100778 42. Gao TT, Long Q, Yang X. Complement factors C1q, C3 and C5b-9 in the
17. Mesquida M, Drawnel F, Fauser S. The role of inflammation in diabetic eye posterior sclera of Guinea pigs with negative lens-defocused myopia. Int J Ophthalmol
disease. Semin Immunopathol (2019) 41(4):427–45. doi: 10.1007/s00281-019-00750-7 (2015) 8(4):675–80. doi: 10.3980/j.issn.2222-3959.2015.04.06

18. Lin HJ, Wei CC, Chang CY, Chen TH, Hsu YA, Hsieh YC, et al. Role of chronic 43. Riddell N, Crewther SG. Novel evidence for complement system activation in
inflammation in myopia progression: clinical evidence and experimental validation. chick myopia and hyperopia models: a meta-analysis of transcriptome datasets. Sci Rep
EBioMedicine (2016) 10:269–81. doi: 10.1016/j.ebiom.2016.07.021 (2017) 7(1):9719. doi: 10.1038/s41598-017-10277-2

19. Han SB, Jang J, Yang HK, Hwang JM, Park SK. Prevalence and risk factors of 44. Zhang Y, Wildsoet CF. RPE and choroid mechanisms underlying ocular growth
myopia in adult Korean population: Korea national health and nutrition examination and myopia. Prog Mol Biol Transl Sci (2015) 134:221–40. doi: 10.1016/
survey 2013-2014 (KNHANES VI). PloS One (2019) 14(1):e0211204. doi: 10.1371/ bs.pmbts.2015.06.014
journal.pone.0211204 45. Zhao F, Wu H, Reinach PS, Wu Y, Zhai Y, Lei Y, et al. Up-regulation of matrix
20. Qi J, Pan W, Peng T, Zeng L, Li X, Chen Z, et al. Higher circulating levels of metalloproteinase-2 by scleral monocyte-derived macrophages contributes to myopia
neutrophils and basophils are linked to myopic retinopathy. Int J Mol Sci (2022) 24(1). development. Am J Pathol (2020) 190(9):1888–908. doi: 10.1016/j.ajpath.2020.06.002
doi: 10.3390/ijms24010080 46. Duffield JS, Lupher M, Thannickal VJ, Wynn TA. Host responses in tissue repair
21. Imtiaz F, Shafique K, Mirza SS, Ayoob Z, Vart P, Rao S. Neutrophil lymphocyte and fibrosis. Annu Rev Pathol (2013) 8:241–76. doi: 10.1146/annurev-pathol-020712-
ratio as a measure of systemic inflammation in prevalent chronic diseases in Asian 163930
population. Int Arch Med (2012) 5(1):2. doi: 10.1186/1755-7682-5-2 47. Lin X, Wang BJ, Wang YC, Chu RY, Dai JH, Zhou XT, et al. Scleral ultrastructure
22. Icel E, Ucak T, Karakurt Y, Yilmaz H, Tasli NG, Turk A. The relation of and biomechanical changes in rabbits after negative lens application. Int J Ophthalmol
neutrophil to lymphocyte ratio and platelet to lymphocyte ratio with high axial myopia. (2018) 11(3):354–62. doi: 10.18240/ijo.2018.03.02
Ocul Immunol Inflamm (2020) 28(3):396–401. doi: 10.1080/09273948.2019.1588334 48. Trouw LA, Daha MR. Role of complement in innate immunity and host defense.
23. Wang X, He Q, Zhao X, Li H, Liu L, Wu D, et al. Assessment of neutrophil-to- Immunol Lett (2011) 138(1):35–7. doi: 10.1016/j.imlet.2011.02.014
lymphocyte ratio and platelet-to-lymphocyte ratio in patients with high myopia. BMC 49. Li S, Qiu Y, Yu J, Shao M, Li Y, Cao W, et al. Serum complement component 3,
Ophthalmol (2022) 22(1):464. doi: 10.1186/s12886-022-02688-1 complement component 4 and complement component 1q levels predict progressive
24. Long Q, Ye J, Li Y, Wang S, Jiang Y. C-reactive protein and complement visual field loss in older women with primary angle closure glaucoma. Br J Ophthalmol
components in patients with pathological myopia. Optom Vis Sci (2013) 90(5):501–6. (2023) 107(6):828–35. doi: 10.1136/bjophthalmol-2021-320541
doi: 10.1097/OPX.0b013e31828daa6e 50. Summers JA, Martinez E. Visually induced changes in cytokine production in
25. Dai L, Yang W, Qin X, Li Y, Cao H, Zhou C, et al. Serum metabolomics profiling the chick choroid. Elife (2021) 10. doi: 10.7554/eLife.70608
and potential biomarkers of myopia using LC-QTOF/MS. Exp Eye Res (2019) 51. Mimura T, Yamagami S, Usui T, Funatsu H, Noma H, Honda N, et al.
186:107737. doi: 10.1016/j.exer.2019.107737 Relationship between myopia and allergen-specific serum IgE levels in patients with
26. Troilo D, Smith EL 3rd, Nickla DL, Ashby R, Tkatchenko AV, Ostrin LA, et al. allergic conjunctivitis. Clin Exp Ophthalmol (2009) 37(7):670–7. doi: 10.1111/j.1442-
IMI - report on experimental models of emmetropization and myopia. Invest 9071.2009.02130.x
Ophthalmol Vis Sci (2019) 60(3):M31–88. doi: 10.1167/iovs.18-25967 52. Wei CC, Kung YJ, Chen CS, Chang CY, Lin CJ, Tien PT, et al. Allergic
27. Yuan J, Wu S, Wang Y, Pan S, Wang P, Cheng L. Inflammatory cytokines in conjunctivitis-induced retinal inflammation promotes myopia progression.
highly myopic eyes. Sci Rep (2019) 9(1):3517. doi: 10.1038/s41598-019-39652-x EBioMedicine (2018) 28:274–86. doi: 10.1016/j.ebiom.2018.01.024

28. Zhu X, Zhang K, He W, Yang J, Sun X, Jiang C, et al. Proinflammatory status in 53. Fan W, Yuan RD. A case of posterior scleritis with transient myopia and
the aqueous humor of high myopic cataract eyes. Exp Eye Res (2016) 142:13–8. increased intraocular pressure. . Int J Ophthalmol (2022) 15(2):360–3. doi: 10.18240/
doi: 10.1016/j.exer.2015.03.017 ijo.2022.02.26
29. Wei Q, Zhuang X, Fan J, Jiang R, Chang Q, Xu G, et al. Proinflammatory and 54. Ugurbas SH, Alpay A, Ugurbas SC. Posterior scleritis presenting with angle
angiogenesis-related cytokines in vitreous samples of highly myopic patients. Cytokine closure glaucoma. Ocul Immunol Inflamm (2012) 20(3):218–20. doi: 10.3109/
(2021) 137:155308. doi: 10.1016/j.cyto.2020.155308 09273948.2012.666613

30. Ando Y, Keino H, Inoue M, Hirota K, Takahashi H, Sano K, et al. Circulating 55. Keino H, Watanabe T, Taki W, Nakashima C, Okada AA. Clinical features and
vitreous microRNA as possible biomarker in high myopic eyes with macular hole. Int J visual outcomes of Japanese patients with scleritis. Br J Ophthalmol (2010) 94
Mol Sci (2022) 23(7). doi: 10.3390/ijms23073647 (11):1459–63. doi: 10.1136/bjo.2009.171744

31. Lai W, Wu X, Liang H. Identification of the potential key genes and pathways 56. Herbort CP, Papadia M, Neri P. Myopia and inflammation. J Ophthalmic Vis Res
involved in lens changes of high myopia. Int J Gen Med (2022) 15:2867–75. (2011) 6(4):270–83.
doi: 10.2147/IJGM.S354935 57. Reddy CV, Brown J Jr., Folk JC, Kimura AE, Gupta S, Walker J. Enlarged blind
32. Xue M, Ke Y, Ren X, Zhou L, Liu J, Zhang X, et al. Proteomic analysis of aqueous spots in chorioretinal inflammatory disorders. Ophthalmology (1996) 103(4):606–17.
humor in patients with pathologic myopia. J Proteomics (2021) 234:104088. doi: 10.1016/s0161-6420(96)30645-3
doi: 10.1016/j.jprot.2020.104088 58. Hofmaier F, Hauck SM, Amann B, Degroote RL, Deeg CA. Changes in matrix
33. Ni Y, Wang L, Liu C, Li Z, Yang J, Zeng J. Gene expression profile analyses to metalloproteinase network in a spontaneous autoimmune uveitis model. Invest
identify potential biomarkers for myopia. Eye (Lond) (2023) 37(6):1264–70. Ophthalmol Vis Sci (2011) 52(5):2314–20. doi: 10.1167/iovs.10-6475
doi: 10.1038/s41433-022-02013-6 59. Wakefield D, Di Girolamo N, Thurau S, Wildner G, McCluskey P. Scleritis:
34. Zhu D, Yang DY, Guo YY, Zheng YF, Li JL, Wang B, et al. Intracameral Immunopathogenesis and molecular basis for therapy. Prog Retin Eye Res (2013)
interleukin 1beta, 6, 8, 10, 12p, tumor necrosis factor alpha and vascular endothelial 35:44–62. doi: 10.1016/j.preteyeres.2013.02.004
growth factor and axial length in patients with cataract. PloS One (2015) 10(2): 60. Bittencourt MG, Kherani S, Ferraz DA, Ansari M, Nasir H, Sepah YJ, et al.
e0117777. doi: 10.1371/journal.pone.0117777 Variation of choroidal thickness and vessel diameter in patients with posterior non-

Frontiers in Immunology 10 frontiersin.org

Xu et al. 10.3389/fimmu.2023.1260592

infectious uveitis. J Ophthalmic Inflammation Infect (2014) 4(1):14. doi: 10.1186/ 86. Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking
s12348-014-0014-z interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discovery (2012) 11
61. Vermeirsch S, Testi I, Pavesio C. Choroidal involvement in non-infectious (8):633–52. doi: 10.1038/nrd3800
posterior scleritis. J Ophthalmic Inflammation Infect (2021) 11(1):41. doi: 10.1186/ 87. Zhao R, Zhou H, Su SB. A critical role for interleukin-1beta in the progression of
s12348-021-00269-9 autoimmune diseases. Int Immunopharmacol (2013) 17(3):658–69. doi: 10.1016/
62. Urzua CA, Herbort CP Jr., Takeuchi M, Schlaen A, Concha-Del-Rio LE, Usui Y, j.intimp.2013.08.012
et al. Vogt-Koyanagi-Harada disease: the step-by-step approach to a better 88. Kowluru RA, Odenbach S. Role of interleukin-1beta in the development of
understanding of clinicopathology, immunopathology, diagnosis, and management: a retinopathy in rats: effect of antioxidants. Invest Ophthalmol Vis Sci (2004) 45
brief review. J Ophthalmic Inflammation Infect (2022) 12(1):17. doi: 10.1186/s12348- (11):4161–6. doi: 10.1167/iovs.04-0633
022-00293-3 89. Wen D, Song W, Liu S, Tan X, Liu F. Upregulated expression of N-methyl-D-
63. Takahashi H, Takase H, Terada Y, Mochizuki M, Ohno-Matsui K. Acquired aspartate receptor 1 and nitric oxide synthase during form-deprivation myopia in
myopia in Vogt-Koyanagi-Harada disease. Int Ophthalmol (2019) 39(3):521–31. Guinea pigs. Int J Clin Exp Pathol (2015) 8(4):3819–26.
doi: 10.1007/s10792-018-0841-2 90. Masjedi A, Hashemi V, Hojjat-Farsangi M, Ghalamfarsa G, Azizi G, Yousefi M,
64. Harada Y, Bhat P, Munk MR, Goldstein DA. Changes in scleral architecture in et al. The significant role of interleukin-6 and its signaling pathway in the
chronic vogt-koyanagi-harada disease. Ocul Immunol Inflamm (2017) 25(1):85–92. immunopathogenesis and treatment of breast cancer. BioMed Pharmacother (2018)
doi: 10.3109/09273948.2015.1057600 108:1415–24. doi: 10.1016/j.biopha.2018.09.177
65. Prakken B, Albani S, Martini A. Juvenile idiopathic arthritis. Lancet (2011) 377 91. Kaur S, Bansal Y, Kumar R, Bansal G. A panoramic review of IL-6: Structure,
(9783):2138–49. doi: 10.1016/S0140-6736(11)60244-4 pathophysiological roles and inhibitors. Bioorg Med Chem (2020) 28(5):115327.
66. Fledelius H, Zak M, Pedersen FK. Refraction in juvenile chronic arthritis: a long- doi: 10.1016/j.bmc.2020.115327
term follow-up study, with emphasis on myopia. Acta Ophthalmol Scand (2001) 79 92. Zahir-Jouzdani F, Atyabi F, Mojtabavi N. Interleukin-6 participation in
(3):237–9. doi: 10.1034/j.1600-0420.2001.790305.x pathology of ocular diseases. Pathophysiology (2017) 24(3):123–31. doi: 10.1016/
67. Taha R, Papadopoulou M, Zetterberg M, Oskarsdottir S, Gronlund MA. Visual j.pathophys.2017.05.005
function and quality of life in A cohort of swedish children with juvenile idiopathic 93. Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat
arthritis. Clin Ophthalmol (2019) 13:2081–91. doi: 10.2147/OPTH.S202486 Immunol (2015) 16(5):448–57. doi: 10.1038/ni.3153
68. Hung KC, Hsueh PY, Wang NK, Su WW, Tan HY. Transient myopic shifting in 94. Ghasemi H. Roles of IL-6 in ocular inflammation: A review. Ocul Immunol
systemic lupus erythematosus. Lupus (2011) 20(3):334–5. doi: 10.1177/ Inflamm (2018) 26(1):37–50. doi: 10.1080/09273948.2016.1277247
0961203310381515 95. Zhao F, Zhou Q, Reinach PS, Yang J, Ma L, Wang X, et al. Cause and effect
69. Yosar J, Whist E. Acute myopic shift in a patient with systemic lupus relationship between changes in scleral matrix metallopeptidase-2 expression and
erythematosus. Am J Ophthalmol Case Rep (2019) 16:100562. doi: 10.1016/ myopia development in mice. Am J Pathol (2018) 188(8):1754–67. doi: 10.1016/
j.ajoc.2019.100562 j.ajpath.2018.04.011
70. Kamath YS, Singh A, Bhat SS, Sripathi H. Acute onset myopia as a presenting 96. Hannocks MJ, Zhang X, Gerwien H, ChashChina A, Burmeister M, Korpos E,
feature of systemic lupus erythematosus. J Postgrad Med (2013) 59(3):245–6. et al. The gelatinases, MMP-2 and MMP-9, as fine tuners of neuroinflammatory
doi: 10.4103/0022-3859.118060 processes. Matrix Biol (2019) 75-76:102–13. doi: 10.1016/j.matbio.2017.11.007
71. Guerriero S, Ciraci L, Cardia G, Vetrugno M. Transient myopic shift as the 97. Nissinen L, Kahari VM. Matrix metalloproteinases in inflammation. Biochim
presenting symptom of systemic lupus erythematosus: a UBM study. Ocul Immunol Biophys Acta (2014) 1840(8):2571–80. doi: 10.1016/j.bbagen.2014.03.007
Inflamm (2010) 18(5):383–4. doi: 10.3109/09273948.2010.498655 98. Kim EK, Choi EJ. Compromised MAPK signaling in human diseases: an update.
72. Bordea MA, Costache C, Grama A, Florian AI, Lupan I, Samasca G, et al. Arch Toxicol (2015) 89(6):867–82. doi: 10.1007/s00204-015-1472-2
Cytokine cascade in Kawasaki disease versus Kawasaki-like syndrome. Physiol Res 99. Cargnello M, Roux PP. Activation and function of the MAPKs and their
(2022) 71(1):17–27. doi: 10.33549/physiolres.934672 substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev (2011) 75
73. Kung YJ, Wei CC, Chen LA, Chen JY, Chang CY, Lin CJ, et al. Kawasaki disease (1):50–83. doi: 10.1128/MMBR.00031-10
increases the incidence of myopia. BioMed Res Int (2017) 2017:2657913. doi: 10.1155/ 100. Barnabei L, Laplantine E, Mbongo W, Rieux-Laucat F, Weil R. NF-kappaB: at
2017/2657913 the borders of autoimmunity and inflammation. Front Immunol (2021) 12:716469.
74. Yu HJ, Chuang MN, Chu CL, Wu PL, Ho SC, Kuo HC. Intravenous doi: 10.3389/fimmu.2021.716469
immunoglobulin treatment in kawasaki disease decreases the incidence of myopia. J 101. Yu H, Lin L, Zhang Z, Zhang H, Hu H. Targeting NF-kappaB pathway for the
Clin Med (2021) 10(7). doi: 10.3390/jcm10071381 therapy of diseases: mechanism and clinical study. Signal Transduct Target Ther (2020)
75. Lei WT, Chang LS, Zeng BY, Tu YK, Uehara R, Matsuoka YJ, et al. 5(1):209. doi: 10.1038/s41392-020-00312-6
Pharmacologic interventions for Kawasaki disease in children: A network meta- 102. Moens U, Kostenko S, Sveinbjornsson B. The role of mitogen-activated protein
analysis of 56 randomized controlled trials. EBioMedicine (2022) 78:103946. kinase-activated protein kinases (MAPKAPKs) in inflammation. Genes (Basel). (2013)
doi: 10.1016/j.ebiom.2022.103946 4(2):101–33. doi: 10.3390/genes4020101
76. Kastelan S, Gverovic-Antunica A, Pelcic G, Gotovac M, Markovic I, Kasun B. 103. Yao B, Wang S, Xiao P, Wang Q, Hea Y, Zhang Y. MAPK signaling pathways in
Refractive changes associated with diabetes mellitus. Semin Ophthalmol (2018) 33(7- eye wounds: Multifunction and cooperation. Exp Cell Res (2017) 359(1):10–6.
8):838–45. doi: 10.1080/08820538.2018.1519582 doi: 10.1016/j.yexcr.2017.06.024
77. Seko Y, Azuma N, Takahashi Y, Makino H, Morito T, Muneta T, et al. Human 104. Lan W, Petznick A, Heryati S, Rifada M, Tong L. Nuclear Factor-kappaB:
sclera maintains common characteristics with cartilage throughout evolution. PloS One central regulator in ocular surface inflammation and diseases. Ocul Surf. (2012) 10
(2008) 3(11):e3709. doi: 10.1371/journal.pone.0003709 (3):137–48. doi: 10.1016/j.jtos.2012.04.001
78. Turk MA, Hayworth JL, Nevskaya T, Pope JE. Ocular manifestations in 105. Steyers CM 3rd, Miller FJ Jr. Endothelial dysfunction in chronic inflammatory
rheumatoid arthritis, connective tissue disease, and vasculitis: A systematic review diseases. Int J Mol Sci (2014) 15(7):11324–49. doi: 10.3390/ijms150711324
and metaanalysis. J Rheumatol (2021) 48(1):25–34. doi: 10.3899/jrheum.190768 106. Nickla DL, Wallman J. The multifunctional choroid. Prog Retin Eye Res (2010)
79. Brown DM, Mazade R, Clarkson-Townsend D, Hogan K, Datta Roy PM, Pardue 29(2):144–68. doi: 10.1016/j.preteyeres.2009.12.002
MT. Candidate pathways for retina to scleral signaling in refractive eye growth. Exp Eye 107. Wu H, Chen W, Zhao F, Zhou Q, Reinach PS, Deng L, et al. Scleral hypoxia is a
Res (2022) 219:109071. doi: 10.1016/j.exer.2022.109071 target for myopia control. Proc Natl Acad Sci U S A. (2018) 115(30):E7091–100.
80. Yu Q, Zhou JB. Scleral remodeling in myopia development. Int J Ophthalmol doi: 10.1073/pnas.1721443115
(2022) 15(3):510–4. doi: 10.18240/ijo.2022.03.21 108. Lin F, Zhao Z, Li F, Qiu Z, Gao X, Song Y, et al. Longitudinal macular retinal
81. Schmid-Schonbein GW. Analysis of inflammation. Annu Rev BioMed Eng. and choroidal microvasculature changes in high myopia. Invest Ophthalmol Vis Sci
(2006) 8:93–131. doi: 10.1146/annurev.bioeng.8.061505.095708 (2021) 62(15):1. doi: 10.1167/iovs.62.15.1
82. Horiuchi T, Mitoma H, Harashima S, Tsukamoto H, Shimoda T. 109. Wang S, Wang Y, Gao X, Qian N, Zhuo Y. Choroidal thickness and high
Transmembrane TNF-alpha: structure, function and interaction with anti-TNF myopia: a cross-sectional study and meta-analysis. BMC Ophthalmol (2015) 15:70.
agents. Rheumatol (Oxford). (2010) 49(7):1215–28. doi: 10.1093/rheumatology/keq031 doi: 10.1186/s12886-015-0059-2
83. Kalliolias GD, Ivashkiv LB. TNF biology, pathogenic mechanisms and emerging 110. Felger JC, Miller AH. Cytokine effects on the basal ganglia and dopamine
therapeutic strategies. Nat Rev Rheumatol (2016) 12(1):49–62. doi: 10.1038/ function: the subcortical source of inflammatory malaise. Front Neuroendocrinol (2012)
nrrheum.2015.169 33(3):315–27. doi: 10.1016/j.yfrne.2012.09.003
84. Yue T, Shi Y, Luo S, Weng J, Wu Y, Zheng X. The role of inflammation in immune 111. Zaborowski MP, Balaj L, Breakefield XO, Lai CP. Extracellular vesicles:
system of diabetic retinopathy: Molecular mechanisms, pathogenetic role and therapeutic composition, biological relevance, and methods of study. Bioscience (2015) 65
implications. Front Immunol (2022) 13:1055087. doi: 10.3389/fimmu.2022.1055087 (8):783–97. doi: 10.1093/biosci/biv084
85. Hu X, Xu MX, Zhou H, Cheng S, Li F, Miao Y, et al. Tumor necrosis factor-alpha 112. Fitzgerald W, Freeman ML, Lederman MM, Vasilieva E, Romero R. Margolis L.
aggravates gliosis and inflammation of activated retinal Muller cells. Biochem Biophys A system of cytokines encapsulated in extraCellular vesicles. Sci Rep (2018) 8(1):8973.
Res Commun (2020) 531(3):383–9. doi: 10.1016/j.bbrc.2020.07.102 doi: 10.1038/s41598-018-27190-x

Frontiers in Immunology 11 frontiersin.org

Xu et al. 10.3389/fimmu.2023.1260592

113. Buzas EI. The roles of extracellular vesicles in the immune system. Nat Rev 120. Walline JJ, Lindsley KB, Vedula SS, Cotter SA, Mutti DO, Ng SM, et al.
Immunol (2023) 23(4):236–50. doi: 10.1038/s41577-022-00763-8 Interventions to slow progression of myopia in children. Cochrane Database Syst Rev
114. Zhang H, Zhang X, Li X. Intraocular exosomes in eye diseases. Curr Mol Med (2020) 1(1):CD004916. doi: 10.1002/14651858.CD004916.pub4
(2022) 22(6):540–8. doi: 10.2174/1566524021666210901122948 121. Yam JC, Li FF, Zhang X, Tang SM, Yip BHK, Kam KW, et al. Two-year clinical
115. Chen CF, Hua K, Woung LC, Lin CH, Chen CT, Hsu CH, et al. Expression trial of the low-concentration atropine for myopia progression (LAMP) study: phase 2
profiling of exosomal miRNAs derived from the aqueous humor of myopia patients. report. Ophthalmology (2020) 127(7):910–9. doi: 10.1016/j.ophtha.2019.12.011
Tohoku J Exp Med (2019) 249(3):213–21. doi: 10.1620/tjem.249.213 122. Ikeda SI, Kurihara T, Toda M, Jiang X, Torii H, Tsubota K. Oral bovine milk
116. Tsai CY, Chen CT, Lin CH, Liao CC, Hua K, Hsu CH, et al. Proteomic analysis lactoferrin administration suppressed myopia development through matrix
of Exosomes derived from the Aqueous Humor of Myopia Patients. Int J Med Sci metalloproteinase 2 in a mouse model. Nutrients (2020) 12(12). doi: 10.3390/
(2021) 18(9):2023–9. doi: 10.7150/ijms.51735 nu12123744
117. You J, Wu Q, Xu G, Gu C, Allen E, Zhu T, et al. Exosomal microRNA profiling 123. Bai L, Shao H, Wang H, Zhang Z, Su C, Dong L, et al. Effects of mesenchymal
in vitreous humor derived from pathological myopia patients. Invest Ophthalmol Vis stem cell-derived exosomes on experimental autoimmune uveitis. Sci Rep (2017) 7
Sci (2023) 64(1):9. doi: 10.1167/iovs.64.1.9 (1):4323. doi: 10.1038/s41598-017-04559-y
118. Elliott RO, He M. Unlocking the power of exosomes for crossing biological 124. Kang M, Choi JK, Jittayasothorn Y, Egwuagu CE. Interleukin 35-producing
barriers in drug delivery. Pharmaceutics (2021) 13(1). doi: 10.3390/ exosomes suppress neuroinflammation and autoimmune uveitis. Front Immunol
pharmaceutics13010122 (2020) 11:1051. doi: 10.3389/fimmu.2020.01051
119. Xiong S, Sankaridurg P, Naduvilath T, Zang J, Zou H, Zhu J, et al. Time spent in 125. Mathew B, Ravindran S, Liu X, Torres L, Chennakesavalu M, Huang CC, et al.
outdoor activities in relation to myopia prevention and control: a meta-analysis and Mesenchymal stem cell-derived extracellular vesicles and retinal ischemia-reperfusion.
systematic review. Acta Ophthalmol (2017) 95(6):551–66. doi: 10.1111/aos.13403 Biomaterials (2019) 197:146–60. doi: 10.1016/j.biomaterials.2019.01.016

Frontiers in Immunology 12 frontiersin.org