Complement and local ocular inflammatory response: Chronic immune factors in myopia

Abstract

Myopia has emerged as a globally pervasive visual disorder, with its incidence rising steadily, particularly among children and adolescents, posing a significant threat to ocular health. Recent research underscores a strong link between chronic inflammatory processes and both the onset and progression of myopia. As a cornerstone of the innate immune system, the complement cascade plays a pivotal role in mediating ocular inflammatory diseases associated with high myopia, including macular degeneration, glaucoma, allergic conjunctivitis, uveitis, and scleritis. Accumulating evidence indicates that complement activation contributes to myopia pathogenesis by orchestrating local inflammatory responses within the eye. This article is a narrative review that synthesizes current evidence on complement-myopia interactions, with a focus on the underlying biological mechanisms and their potential as therapeutic targets for both preventing and managing myopia.

Keywords

Complement myopia ocular diseases inflammation high myopia

Introduction

Myopia is a prevalent visual disorder with a rapidly rising global incidence, especially among children and adolescents.¹ According to the World Health Organization (WHO), nearly half of the world's population is projected to develop myopia by 2050, with ∼10% progressing to high myopia (HM) (defined as −6.00 D or worse).² HM substantially elevates the risk of severe visual impairment and is linked to sight-threatening conditions such as retinal detachment, macular degeneration, and glaucoma.³ Consequently, preventing and controlling myopia has emerged as a critical global public health priority. Although the onset and progression of myopia involve complex interactions among genetic, environmental, and behavioral factors, recent research has increasingly focused on the potential role of local ocular inflammation and immune responses.^4,5 Chronic ocular inflammation, particularly the altered expression of inflammatory mediators in the retina and sclera, is thought to contribute to axial elongation and scleral remodeling—key processes in myopia development.¹ Among these immune mechanisms, the complement system, a cornerstone of innate immunity, plays a critical regulatory role in various ocular diseases.⁶ Emerging evidence suggests that mild chronic inflammation in the sclera and retina of myopic eyes may upregulate complement components C3 and C5, potentially driving myopia onset and progression.^1,7 This narrative review aims to summarize the involvement of the complement system in chronic ocular inflammation, emphasizing its immunoregulatory functions in the retina and sclera, and to explore its potential contributions to the pathogenesis and progression of myopia. To ensure a comprehensive overview, relevant literature published up to June 2025 was retrieved from databases including PubMed, Web of Science, and Scopus using keywords such as “complement,” “myopia,” “ocular diseases,” and “inflammation.” The review adheres to the Scale for the Assessment of Narrative Review Articles guidelines to ensure structural clarity and academic rigor.⁸

Overview of the complement system and pathway mechanism

The complement system, a crucial part of the innate immune system, comprises a set of plasma proteins circulating in body fluids and their membrane-bound receptors.⁹ It drives inflammation by directly eliminating pathogens and producing anaphylatoxins via the membrane attack complex (MAC), while also facilitating phagocytosis by immune cells and modulating adaptive immune responses.¹⁰ Complement activation occurs through three primary pathways: the classical pathway, the alternative pathway (AP), and the lectin pathway. These pathways converge to generate C3 and C5 cleavage products, including C3a and C5a, which are potent pro-inflammatory fragments that recruit and activate immune cells, further amplifying the inflammatory response (Figure 1).¹¹ The classical pathway is primarily initiated by the antigen-antibody complex, where the C1 complex (C1q, C1r, and C1s) binds to IgG or IgM antibodies, leading to C4 and C2 cleavage and the formation of the classical C3 convertase (C4bC2b).^12,13 C1q, the initiating molecule of this pathway, consists of six heterotrimers, each containing an A-, B-, and C-chain encoded by C1qa, C1qb, and C1qc, respectively.¹⁴ The lectin pathway is triggered by mannose-binding lectin, which recognizes pathogen-associated carbohydrate structures and activates MASP-1 and MASP-2 to cleave C4 and C2.^12,13 The AP is initiated by the spontaneous hydrolysis of C3, producing C3(H₂O), which combines with Factor B and Factor D to form the alternative C3 convertase (C3bBb).^12,13 Key AP components, Factor B (CFB) and Factor D (CFD), are involved in both initiation and amplification, while Factor H (CFH) acts as a soluble regulator that inhibits AP activation in the fluid phase.¹⁵ Unlike the classical pathway, which bridges innate and adaptive immunity, the AP responds rapidly to non-specific pathogen recognition.^12,13 The C3 convertase cleaves the abundant plasma protein C3 into C3a and C3b; C3b then binds to microbial surfaces to propagate the AP activation.¹⁶ Upon binding to surface-bound C3b, CFB is cleaved by CFD into Ba and Bb, with Bb remaining attached to C3b to form the alternative C3 convertase complex (C3bBb), which is stabilized by properdin.^16,17 C3 activation subsequently leads to C5 convertase formation, which cleaves C5 into C5a and C5b, and the continuous recruitment of C5b with C6, C7, C8, and C9 binds to the membrane surface to form the MAC (C5b-9), causing membrane disruption and ultimately cell activation or lysis.^16,17 Anaphylatoxins (C3a and C5a) bind to their respective receptors on target cells to triggering cell-specific responses.^16,17

Figure 1.

The complement system. The complement system can be activated via three distinct pathways: classical pathway, lectin pathway, and alternative pathway, and all three pathways converge at a critical step—the formation of C3 convertase. Once generated, C3 convertase cleaves C3 into two fragments: C3a and C3b, and C3b plays a pivotal role in further advancing the cascade by promoting the generation of C5 convertase, which cleaves C5 to C5a and C5b. The anaphylatoxins C3a and C5a exert their effects by binding to specific receptors on target cells, triggering the production of downstream inflammatory mediators and thereby driving inflammation. On the other hand, C5b initiates the sequential recruitment of C6, C7, C8, and C9, culminating in the formation of the membrane attack complex (MAC or C5b-9), which creates pores in the target cell membrane, ultimately leading to cell lysis. In ocular tissues, these complement effectors contribute to inflammation through multiple mechanisms, and they activate the NLRP3 inflammasome and upregulate cytokine production, which subsequently leads to the activation of matrix metalloproteinases (MMPs) and scleral remodeling. Additionally, MAC-induced damage to the retinal pigment epithelium (RPE) triggers neuroinflammation, resulting in retinal thinning. Collectively, these processes drive axial elongation and structural changes in the eye associated with myopia.

The activation of the complement system demands stringent regulation to shield host tissues from inadvertent damage. Key regulatory proteins, including C1 inhibitor, CFH, and membrane cofactor protein (MCP), play pivotal roles in preserving complement homeostasis by inhibiting various stages of complement activation.^17,18 However, any disruption to this delicate balance can result in overactivation of the complement system, leading to self-tissue injury, and such overactivation is implicated in a range of immune-mediated diseases, encompassing autoimmune disorders, chronic inflammatory conditions, and multiple ocular pathologies.¹⁸ Within the eye, the complement system is critically involved, particularly in the retina, sclera, and choroid.¹⁹ It is primarily expressed by various resident retinal cells, such as neuroretinal cells, retinal pigment epithelial (RPE) cells, RPE/choroid, vascular cells, fibroblasts, Müller glial cells, microglia, as well as corneal and conjunctival epithelial cells, and so on.^20–22 Under inflammatory conditions, Müller cells and microglia can upregulate complement-related molecules, including C1s, C3, C4, C3aR, and C5aR1, thereby perpetuating inflammation and driving tissue remodeling.^20,23 Although the eye, as an immune-privileged organ, has unique immune regulatory mechanisms to restrict pathogen entry and maintain tissue-specific immune tolerance.²⁴ Complement system dysregulation emerges as a key factor in the pathogenesis of various ocular diseases.²⁵

Pathophysiology of myopia and immune responses

The pathogenesis of myopia involves abnormal ocular axis elongation, scleral remodeling, and intricate signal transduction between the retina and sclera.²⁶ Beyond traditional optical and mechanical factors, the immune system, particularly chronic inflammatory responses, plays a pivotal role in myopia development.¹ The sclera, the primary site of axial elongation, undergoes remodeling due to inflammation, which induces structural alterations such as reduced collagen fiber content and decreased elasticity, thereby promoting scleral expansion and axial elongation.²⁷ Scleral remodeling is believed to be regulated by complex biochemical signals, including signaling factors (such as TGF-β) released by the retina.²⁸ The retina detects optical defocus and transmits regulatory signals to the sclera, thereby modulating ocular growth.²⁹ Moreover, the retinal dopamine signaling system is crucial for axial development, with reduced dopamine levels linked to myopia due to its inhibitory effect on excessive ocular growth.³⁰ In the context of immune involvement, low-grade chronic inflammation in the retina and sclera is observed during myopia progression.³¹ Clinical studies have reported significantly elevated levels of proinflammatory cytokines, including interleukin-6 (IL-6), interferon-gamma (IFN-γ), IFNγ-inducing protein 10 (IP-10), eosinophil chemotactic factors, and macrophage inflammatory protein-1α (MIP-1α), in the vitreous fluid of patients with HM compared to non-myopic individuals.³² Additionally, aqueous humor levels of IL-6, matrix metalloproteinase-2 (MMP-2), soluble intercellular adhesion molecule-1 (sICAM-1), monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-beta 2 (TGF-β2) correlate positively with axial length in myopic eyes.^4,33 Analysis of aqueous humor microRNAs in HM has revealed abnormal expression patterns involving inflammatory signaling pathways such as TNF, mitogen-activated protein kinase (MAPK), PI3K-Akt, and HIF-1 signaling pathways.³⁴ These pathways, including MAPK and nuclear factor kappa B (NF-κB), are thought to contribute to myopia progression.³⁵ Animal experiments have demonstrated that visual stimulation in HM increases CCL2 expression in photoreceptor cells (PRCs) and retinal ganglion cells (RGCs), promoting monocyte/macrophage infiltration, disrupting the blood-ocular barrier, and inducing local tissue damage, thereby exacerbating ocular inflammation.³⁶ These inflammatory responses may regulate ocular axis elongation through immune-mediated mechanisms. Current studies suggest that the visual mechanisms regulating refractive development are primarily located in the retina.³⁷ Where immune cells, particularly microglia, play a key role. Microglia, as resident innate immune cells, become activated in response to injury or stress, releasing pro-inflammatory cytokines like TNF-α and IL-1β.³⁸ Related pro-inflammatory factors can also exacerbate retinal microvascular and neurodegeneration in myopia.³⁹ Additionally, certain pro-inflammatory cytokines in the retina, such as interleukin-6 (IL-6), may directly contribute to scleral remodeling by promoting MMPs secretion by scleral fibroblasts.⁴⁰ Furthermore, certain inflammatory diseases have been linked to myopia progression, with inflammatory molecular mechanisms potentially originating in the retina and inducing scleral remodeling through the choroid.^37,41

As a vital part of the innate immune system, the complement system is central to regulating ocular axial growth by modulating scleral immune responses.⁴² Recent research reveals abnormal expression of several complement cascade components, notably from the classical and APs, such as C3, C5b-9, CFB, and CFH, in patients with pathological myopia and experimental myopia models.^42,43 Elevated levels of C5b-9, C1q, and C3 in posterior scleral fibroblasts of myopic animal models suggest a direct role for the complement system in myopia development.⁴² Local complement activation in the retina and choroid boosts C3 and C5 production, recruiting and activating microglia and macrophages, thereby amplifying ocular inflammation.^7,44 Complement activation also triggers downstream inflammatory pathways; for instance, increased C5b-9 levels in myopic animal models are linked to NLRP3 inflammasome activation.⁴⁵ This sustained, low-grade inflammation drives remodeling of the scleral extracellular matrix, altering collagen density and elasticity, and contributing to excessive axial elongation.⁴⁵ Furthermore, abnormal expression of complement regulatory proteins, such as CD55, which inhibits C3 convertase formation and is implicated in various inflammatory disorders, has been detected in the retinas of myopic models.⁷ These findings underscore the complement system as a crucial inflammatory mechanism connecting retinal immune activation to scleral structural changes in myopia. Although markers of complement activation are elevated in both experimental and clinical myopia models, discerning cause from effect remains difficult. Complement and complement regulatory gene expression is upregulated under oxidative stress and inflammatory conditions.⁴³ It is plausible that complement dysregulation contributes to early immune activation and tissue remodeling; however, it is equally possible that tissue stress from axial elongation leads to secondary complement activation, akin to observations in other degenerative eye diseases.^43,46–48 Clarifying this temporal relationship necessitates further longitudinal and mechanistic investigations.

Complement system and inflammatory responses in ocular diseases

Research on a range of ocular diseases has revealed that complement system activation is not only pivotal for ocular immune defense but also intricately linked to disease development. The following section offers an in-depth examination of the complement system's role in ocular conditions, encompassing age-related macular degeneration (AMD), glaucoma, conjunctivitis, uveitis, and scleritis (Table 1).

Table 1.

Summary of complement pathway activation in major ocular diseases and potential links to myopia.

Ocular disease	Activated complement pathway(s)	Key complement components	Functional outcome	Relevance to myopia
AMD	Classical, alternative, and lectin (less)^49–51	C1q, CFH, CFB, C3, C5, and MAC^50,52	RPE degeneration, choroidal neovascularization^53,54	Shared features of low-grade inflammation, extracellular matrix remodeling, and neovascularization in pathological myopia-associated CNV^54–57
Glaucoma	Classical, lectin, and alternative (mild activation)⁵⁸	C1q, C3, C3a, MAC, and CFH^58–60	Retinal ganglion cell loss, optic nerve damage⁶¹	High myopia is associated with RNFL thinning and retinal stress, possibly overlapping with RGC degeneration and complement-driven neuroinflammation in glaucoma^62–65
Conjunctivitis	Complement pathway involvement in allergic conjunctivitis is not fully defined, but all three pathways (classical, lectin, and alternative) may contribute to allergic inflammation⁶⁶	C3a, C3, and CFH⁶⁷	Histamine release, mast cell activation⁶⁷	Immune sensitization relevant to myopic inflammation^68–70
Uveitis	Classical and alternative^71,72	C3b, CFH, MAC, and C4^71,73,74	Inflammatory cytokine upregulation, immune cell infiltration^74–76	Highlights complement-mediated inflammation^77–79
Scleritis	Classical and alternative^80–82	C1q and MAC^80,81	Stromal inflammation, scleral thinning^80,83	May inform immune contribution to scleral remodeling^31,42,83

AMD: age-related macular degeneration; CFH: component Factor H; CFB: component Factor B; CFD: component Factor D; MAC: membrane attack complex; RPE: retinal pigment epithelial; CNV: choroidal neovascularization; RNFL: retinal nerve fiber layer; RGC: retinal ganglion cell.

Complement in AMD

AMD is a leading cause of blindness, primarily affecting the elderly and influenced by genetic factors.⁸⁴ Extensive research has underscored the central role of the complement system in AMD pathogenesis.⁸⁵ Genetic studies have linked AMD to single-nucleotide polymorphisms (SNPs) in complement-related genes, notably C3, CFH, and CFB.^86–88 CFH acts as a negative regulator of the AP, while CFB serves as a positive activator.^86,87 The study found that while the rs1410996 variant in CFH increases AMD risk, the rs641153 variant in CFB is protective due to its role in reducing AP activity.⁸⁹ In AMD patients, increased deposition of complement proteins, such as C3 and C5b-9, is observed in the RPE, Bruch's membrane, and choroid, indicating sustained complement activation.⁴⁹ AMD presents in two types: dry AMD, characterized by atrophy, and wet AMD, marked by neovascularization, with the latter involving the formation of choroidal neovascularization (CNV).⁹⁰ Elevated concentrations of C3a, C4a, and C5a have been documented in patients afflicted with neovascular AMD, particularly among those presenting with subretinal fibrosis.⁹¹ In murine models of CNV, CR2-fH—a fusion protein comprising a C3d-targeting domain fused with regulatory domains of CFH—has been demonstrated to expedite the repair process of CNV, which is achieved through selective inhibition of the AP, thereby mitigating retinal damage and fostering tissue recovery.⁹⁰ Although C3a and C5a are downstream anaphylatoxins that can be generated through all three complement pathways, the AP functions as a major amplification loop.⁹⁰ Targeting the AP using agents such as CR2-fH inhibitors helps to curtail sustained inflammation at the lesion site, whereas blockade of C3aR or C5a does not influence the upstream cascade but may only confer limited immunosuppression.⁹⁰ Similarly, in geographic atrophy (GA), persistent activation of C3a, C5a, and C5b-9 contributes to inflammation and retinal cell death, underscoring complement inhibition as a promising therapeutic strategy for GA.⁹² The causal involvement of the complement system in AMD and CNV pathogenesis is corroborated by several knockout mouse studies. Mice deficient in C3 (C3⁻/⁻) exhibit a significantly diminished incidence of CNV.⁹³ Analogously, deletion of anaphylatoxin receptors in C3aR⁻/⁻ and C5aR⁻/⁻ mice results in attenuated CNV formation, indicating that C3a and C5a signaling promotes pathological angiogenesis.⁹⁰ Studies utilizing factor B-deficient (Cfb−/−) mice have revealed substantially reduced CNV lesion size compared to wild-type animals, whereas the size of CNV increases significantly following the injection of an adequate amount of CFB serum into CFB-KO mice.⁹⁴ In Cfh⁻/⁻ mice, the absence of CFH leads to uncontrolled C3 activation, resulting in C3 deposition in the retina, photoreceptor degeneration, and impaired visual function.⁹⁵ Notably, even in chimeric mice expressing human CFH risk variants on a Cfh⁻/⁻ background, early AMD-like changes such as basal laminar deposits persist, indicating that these human CFH variants are unable to fully regulate complement activity in the retina.⁹⁶

Notably, the complement-mediated mechanisms observed in AMD demonstrate substantial parallels with the pathological alterations seen in HM. CNV is a frequent occurrence in patients suffering from both AMD and pathological myopia, and genetic factors associated with AMD have been implicated in the development of myopic CNV.^55,56 Aberrant activation of the complement system precipitates RPE damage and CNV formation, as corroborated by elevated levels of MAC in the RPE and choroidal vasculature of AMD patients.⁵⁴ MAC contributes to CNV formation by inducing RPE cell lysis and stimulating the release of proangiogenic cytokines, including vascular endothelial growth factor (VEGF).⁵⁷ These underlying mechanisms are also implicated in the pathogenesis of myopic CNV, suggesting that chronic complement activation within the outer retina and choroid may represent a shared pathogenic cascade in both AMD and pathological myopia. The convergence of complement dysregulation in these two conditions underscores the existence of a common immunopathological process, wherein sustained low-grade inflammation driven by complement activation plays a pivotal role in extracellular matrix remodeling and neovascularization, thereby contributing to the progression of both diseases.

Complement in glaucoma

Glaucoma is a neurodegenerative ocular disorder marked by optic nerve damage and consequent vision loss.⁹⁷ Despite extensive research, the precise etiology of glaucoma remains elusive; however, a growing body of evidence underscores the pivotal role of the complement system in driving the chronic inflammatory response within the optic nerve.⁹⁸ Clinical investigations have unveiled complement activation in exfoliation glaucoma, with patients exhibiting significantly elevated levels of complement inhibitors, including clusterin and vitronectin, as well as complements C3a and soluble C5b-9 in their aqueous humor of patients compared to healthy controls.⁵⁹ Notably, C1q has been implicated in the early stages of optic nerve damage, and molecular clustering analysis has further revealed an upregulated expression of genes associated with the complement cascade, such as C1qa, during the initial phases of glaucoma.⁹⁹ One of the key mechanisms through which the complement system contributes to glaucoma pathogenesis is by promoting the apoptosis of RGC.⁶¹ Studies have demonstrated abnormal activation of the complement system within the RGCs and optic nerves of glaucoma patients, accompanied by increased deposition of C1q and C3.^100,101 The activation of C1q initiates the classical pathway, leading to the cleavage of C3 and C5 and the subsequent generation of inflammatory mediators, which exacerbate RGC apoptosis by amplifying neuroinflammation.⁶⁰ Furthermore, the amplification of the complement cascade enhances immune responses, and increased deposition of the MAC deposition has been implicated in RGC apoptosis in glaucoma.¹⁰² Complement depletion has been illustrated to suppress calcium (Ca²⁺) influx in RGCs, potentially preventing cell death.¹⁰² It is also worth noting that early degeneration of dendrites and synapses precedes RGC death and may contribute to visual dysfunction.^103–105 In genetic mouse models of glaucoma and induced high intraocular pressure (IOP) rat models, complement C1qa has been found to mediate dendritic atrophy and synaptic loss before damage occurs to the RGC soma or axon.¹⁰⁵ C1q deposition on synapses promotes excessive microglial activation and enhances synaptic phagocytosis, while inhibiting the classical pathway of the complement cascade can prevent early dendritic and synaptic degeneration in glaucoma.¹⁰⁵ Targeting C1q specifically with ANX007, a humanized monoclonal antibody, effectively blocks classical complement activation, thereby reducing synaptic loss and microglia-mediated inflammatory responses.¹⁰⁶ Although the classical pathway appears to be the primary route of complement activation in glaucoma, both the AP and the lectin pathway also exhibit mild activation.⁵⁸ In transgenic βB1-CTGF mice, a model of primary open-angle glaucoma, an increase in CFB⁺ cells was observed in the ganglion cell layer (GCL), along with elevated Cfb mRNA expression.⁵⁸ Additionally, patients with primary open-angle glaucoma exhibit, reduced levels of CFH in their aqueous humor, suggesting impaired regulation of the AP and a predisposition to excessive complement activity.¹⁰⁷

Interestingly, a growing body of evidence suggests a pathophysiological connection between myopia and glaucoma, notably through shared structural and inflammatory changes.⁶² Clinical and imaging studies reveal that HM is linked to retinal nerve fiber layer (RNFL) thinning, a key indicator of glaucomatous damage.⁶³ In the form-deprivation myopia (FDM) guinea pig model, long non-coding RNAs (lncRNAs) in RGCs have been found to induce RGC damage by suppressing the cGMP/PKG and apelin signaling pathways, mirroring the neurodegeneration seen in glaucoma.⁶⁴ Moreover, intrinsically photosensitive retinal ganglion cells (ipRGCs) are crucial for ocular development and myopia progression, with their functional changes influencing myopia onset and advancement.⁶⁵ The involvement of C1q, C3a, C5a, and MAC in synaptic degeneration and microglial activation implies that complement-mediated retinal remodeling is a common pathophysiological mechanism in both conditions. These similarities further bolster the hypothesis that complement system dysregulation, especially via the classical pathway, not only drives glaucomatous neurodegeneration but may also contribute to the retinal structural changes observed in pathological myopia.

Complement in conjunctivitis

Conjunctivitis arises from diverse pathogens and immune responses, presenting with conjunctival vascular dilation and often mucous or purulent secretions.¹⁰⁸ Haemophilus influenzae can induce conjunctivitis through complement-mediated cytotoxicity.¹⁰⁹ Among non-infectious forms, allergic conjunctivitis (AC) is highly prevalent, primarily triggered by an IgE-mediated type I hypersensitivity reaction.¹¹⁰ During this process, CD4⁺ Th2 cells secrete cytokines that prompt B cells to generate allergen-specific IgE, involving mast cells, histamine release, eosinophils, and other immune elements.¹¹¹ Clinical studies have reported elevated levels of C3 and CFB in the tears of patients with vernal conjunctivitis (VC) and giant papillary conjunctivitis (GPC), with most C3 produced locally by conjunctival tissues, and the activation of the local complement system and the generation of the anaphylatoxin C3a stimulate basophils and mast cells to release inflammatory mediators.⁶⁷ Research indicates that blocking the Th2 signaling pathway in a rat model of AC reduces serum IgE levels, decreases mast cell degranulation and eosinophil infiltration, and alleviates conjunctival inflammation symptoms.¹¹² Similarly, C3-deficient mice demonstrate significantly reduced antigen-specific Th1 and Th2 responses after both epicutaneous and intraperitoneal sensitization.¹¹³ In patients with chronic cicatricial conjunctivitis, elevated complement proteins and pro-inflammatory cytokines suggest that complement activation contributes to chronic inflammation and fibrosis.¹¹⁴ Beyond ocular inflammation, the complement system is crucial for immune regulation, inflammatory amplification, and airway remodeling in allergic diseases like asthma.¹¹⁵ Complement-derived anaphylatoxins C3a and C5a enhance IgE-mediated hypersensitivity reactions, acting as powerful effectors in type I allergy pathways.¹¹⁵ Additionally, C1q binds to human dermatophagoides allergens, and in dendritic cell (DC)-specific C1qa-deficient mouse models, allergen recognition is impaired, leading to reduced asthma-associated inflammatory responses.¹¹⁶

AC has also been linked to the development of myopia, with studies revealing that AC patients with indoor allergen-specific IgE tend to have a higher degree of myopia compared to healthy individuals.⁶⁸ Furthermore, animal models of AC demonstrate that compromised corneal tight junctions lead to elevated levels of intraocular inflammatory cytokines, potentially due to increased cytokine permeability, and high concentrations of MCP-1, IL-6, IL-8, and TNF-α are considered potential drivers of retinal inflammation and myopia progression.⁶⁹ In allergic responses, the binding of complement components C3a and C5a to receptors on mast cells and basophils activates the complement system, which synergizes with classical IgE-mediated reactions, so AC may facilitate IgE's involvement in myopia progression through complement activation.^70,115

Complement in uveitis and scleritis

Uveitis is an inflammatory ocular condition characterized by immune-mediated damage to the uvea, retina, and vitreous body.¹¹⁷ The component cascade, a vital part of innate immunity, significantly contributes to uveitis pathogenesis.⁷⁶ Elevated plasma C3d levels and increased C3 and CFB concentrations in the aqueous humor of uveitis patients suggest complement activation, often triggered by immune complex deposition in uveal tissue.^73,75 In non-infectious uveitis (NIU), the high expression of C3 and CFH in the aqueous humor indicates that dysregulation of the alternative complement pathway plays a crucial role in disease development.⁷¹ Complement activation products further activate macrophages and microglia, prompting the release of both anti-inflammatory and pro-inflammatory cytokines, which worsen ocular inflammation.⁷¹ In the EAU model, elevated plasma and aqueous humor levels of C3a and MAC (C5b-9) were observed, and proteomic analysis revealed that complement signaling pathways interact with inflammatory pathways like NF-κB and PI3K-Akt, collectively driving uveitis pathology.¹¹⁸ Additionally, C4 has been indicated to influence T-cell-mediated uveitis, with its deficiency reducing retinal T-cell infiltration and inflammation.⁷⁴ Moreover, the complement C1q subcomponent subunit B has been identified as a key protein in aqueous humor-derived exosomes from patients with Vogt-Koyanagi-Harada disease and Behçet's uveitis.⁷²

While uveitis is not typically considered a direct cause of myopia, growing evidence suggests a possible link. A retrospective cohort study has revealed a higher prevalence of myopia among uveitis patients, likely attributable to chronic inflammation.⁷⁷ In cases of active Behçet's disease (BD)-associated uveitis, both complement factors and inflammatory cytokines are markedly elevated.⁷⁸ Notably, increased expression of C3aR has been detected in peripheral blood mononuclear cells (PBMCs) from BD patients, and stimulation with C3a triggers the production of IL-6, IL-1β, and TNF-α—cytokines previously linked to myopia development.⁷⁹ These shared inflammatory mediators imply that persistent complement-driven inflammation in uveitis may contribute to retinal and scleral immune activation, potentially influencing the progression of myopia.

Scleritis, a serious immune-mediated inflammation of the scleral tissue, frequently occurs alongside systemic autoimmune diseases like rheumatoid arthritis and vasculitis.¹¹⁹ Complement components, including C1–C6 and CFB, are present in the sclera and can be activated by immune complex deposition.⁸¹ Histological analyses have revealed a higher concentration of C1 in the anterior sclera, which may explain the greater prevalence of anterior scleritis.⁸² Scleral fibroblasts can increase the expression of C1, C2, and C4 in response to interferon-γ stimulation, underscoring their role in local immune reactions.⁸³ Increased intraocular inflammation linked to scleritis or systemic autoimmune conditions can influence myopia progression.³¹ In a guinea pig model of lens-induced myopia, an upregulation of C1q, C3, and C5b-9 in posterior scleral fibroblasts was observed, indicating that complement activation plays a role in scleral remodeling during myopia development.⁴² Although scleritis is not usually a direct cause of myopia, complement-driven fibroblast activation and extracellular matrix remodeling may reflect the pathological processes of scleral thinning and biomechanical changes seen in myopia.

Taken together, research on uveitis and scleritis highlights complement activation's ability to drive inflammatory and structural changes throughout both the anterior and posterior regions of the eye. Although their precise role in myopia development is still being clarified, these conditions provide crucial insights into how complement dysregulation can disrupt ocular immune balance, remodel the extracellular matrix, and possibly contribute to axial elongation.

Potential role of the complement system in myopia development

Complement activation and progression of myopia

Overactivation or dysregulation of the complement system is implicated in various chronic inflammatory diseases.¹²⁰ Myopia is characterized by an increase in axial length, or expansion of the vitreous cavity, accompanied by thinning of the fibrous scleral tissue and reduced choroidal vascular thickness.^121,122 During myopia progression, the complement system activation affects ocular tissues, particularly the sclera and retina, through multiple mechanisms, potentially triggering or exacerbating abnormal axial elongation. Key complement activation products, C3a and C5a, are potent inflammatory mediators that recruit immune cells and promote inflammatory responses.¹⁰ Low-grade chronic inflammation has been noted in myopic eyes, especially in the retina and sclera.¹ In animal models of myopia, there is upregulation of C1q, C3, and C5b-9 has been detected in posterior scleral fibroblasts.⁴² C3a, binding to its receptor C3aR, influences the proliferation and function of human scleral fibroblasts (HSFs), leading to increased secretion of MMPs, which promote collagen fiber degradation and scleral expansion.¹²³ Animal studies indicate that, compared to healthy wild-type (WT) mice, C6 knockout (C6-KO) mice, which lacking C5b-9, exhibit less myopic shift and axial elongation.⁴⁵ Furthermore, in these C6-KO mice, levels of C5b-9, MMP-2, NLRP3, caspase-1, and IL-1β in ocular tissues are significantly lower than in myopia model mice, suggesting that C5b-9 contributes to scleral remodeling via activation of the NLRP3 inflammasome.⁴⁵ CD55 (decay-accelerating factor) plays a regulatory role in complement activation by inhibiting C3 convertase formation, thereby downregulating inflammation and suppressing myopia development.⁷ Research has demonstrated that CD55-Fc inhibits myopia progression by suppressing C3 and C5 activation and reducing the expression of myopia-specific cytokines, such as MMP-2 and TGF-β in TNF-α-induced myopia animal models.⁷ Excessive complement activation also disrupts the normal function of retinal neurons and glial cells. In some animal models, complement dysregulation is closely linked to retinal neuronal injury.¹²⁴ During myopia progression, vitreous elongation correlates with a decrease in RGC and astrocyte density around the optic disc, along with increased expression and intensity of glial fibrillary acidic protein (GFAP).¹²⁵ The cornea also undergoes changes during myopia progression, as axial elongation is accompanied by alterations in corneal curvature and biomechanical properties.¹²⁶ Proteomic analysis of the corneal stroma has identified changes in proteins associated with complement-mediated inflammation, extracellular matrix remodeling, and mitochondrial energy metabolism as potential key factors in myopia development.¹²⁷

Complement and HM

HM is a severe refractive error marked by significant axial elongation, often accompanied by complications like retinal degeneration, choroidal atrophy, and scleral thinning.¹²⁸ Research indicates that chronic inflammatory responses are more pronounced in highly myopic eyes and are closely linked to complement system activation.⁵³ Proteomic analysis of aqueous humor from HM patients has demonstrated elevated levels of complement component C3 and α-2-HS-glycoprotein.¹²⁹ Both patients and experimental models of HM exhibit significant intraocular complement activation, with the classical and alternative complement pathways implicated in neuronal and vascular degeneration in the macular retina and peripapillary region.⁴³ During the pathological progression of HM, complement activation not only accelerates scleral remodeling but also contributes to retinal and choroidal damage. For contributes, aqueous humor from HM patients contains notably high levels of CFH, which is negatively correlates with choroidal thickness.⁴⁷ As myopic maculopathy progresses, CFH levels rise, particularly in eyes with choroidal atrophy and neovascularization, possibly reflecting a compensatory response to chronic complement activation and tissue stress rather than enhanced complement inhibition.⁴⁷ A significant negative correlation between CFH concentration and choroidal thickness suggests that increased CFH expression is associated with disease severity.⁴⁷ Reducing C3 activation and C3a generation has been illustrated to suppress VEGF-mediated angiogenesis in RPE cells while increasing mRNA levels of pigment epithelium-derived factor, thereby inhibiting pathological neovascularization.¹³⁰ The delicate vascular systems of the retina and choroid are vulnerable to complement-mediated inflammatory responses, which contribute to microvascular disruption and leakage.¹³¹ This chronic vascular damage is a key factor in retinal degeneration associated with HM.¹³² Additionally, the MAC, a product of complement activation, can directly attack cell membranes, leading to cell lysis and tissue damage.⁵⁴ At sublytic concentrations, MAC induces the release of cytokines like VEGF, promoting CNV, while higher levels cause direct cell damage, contributing to choroidal ruptures and structural changes associated with myopic CNV.⁵⁴ Similarly, proteomic analysis of aqueous humor from patients with myopic atrophic maculopathy and pathological myopic choroidal neovascularization has identified elevated levels of GFAP and complement-related molecules.¹³³ HM shares pathological processes with certain inflammatory retinal diseases, such as retinal detachment and macular degeneration.¹³⁴ Proteomic analysis of vitreous fluid from patients with diabetic retinopathy, AMD, and retinal detachment has revealed complement and coagulation-related biomarkers, including complement C2 and prothrombin.¹³⁵

Complement and genetic susceptibility to myopia

Recent research has delved into the intricate genetics of myopia and refractive errors, highlighting the dynamic interplay between environmental exposures and genetic predispositions in shaping refractive development.¹³⁶ Growing evidence points to a potential association between the complement system and genetic susceptibility to myopia, with genetic variations potentially influencing complement system function and, consequently, an individual's predisposition to myopia. Transcriptome analyses have pinpointed the complement C7 gene in myopia animal models, and a meta-analysis of transcriptome datasets from a chick model with optically induced ametropia has revealed transcriptional activation of the complement system during myopia induction.^46,137 Differential gene expression and enrichment studies on the sclera of myopic model mice have demonstrated upregulation of key complement pathway genes, including C1qa, C1qb, Masp1, and Cfb.⁴⁵ In summary, while the existing literature suggests a link between genetic susceptibility to myopia and the complement system, research in this domain remains relatively nascent and warrants further exploration.

Anti-myopia interventions and potential modulation of inflammatory pathways

Low-dose atropine is currently among the most widely employed pharmacological treatments for myopia, aimed at slowing axial elongation.¹³⁸ While the precise mechanisms underlying atropine's efficacy remain incompletely elucidated, mounting evidence indicates that it mitigates myopia progression by modulating ocular inflammation and tissue remodeling pathways.^77,139 Experimental studies have demonstrated that atropine suppresses inflammatory markers such as NF-κB, IL-6, TNF-α, and c-Fos in form-deprivation myopia models, leading to significant inhibition of axial elongation.⁷⁷ Additionally, compounds like dicarboxylic acid and resveratrol have been indicated to reduce the expression of inflammatory factors in ARPE-19 cells, primarily by inhibiting the PI3K/AKT and NF-κB signaling pathways, thereby decelerating myopia progression in animal models.^140,141 Although direct evidence linking atropine to complement inhibition is currently scarce, its broad immunomodulatory effects, particularly through NF-κB suppression, may indirectly influence complement activation, given the well-established interplay between cytokines and the complement system. Future research is warranted to explore whether atropine or similar interventions can modulate complement-mediated inflammatory cascades in the myopic eye, potentially opening new avenues for therapeutic intervention.

Conclusion

In recent years, growing evidence has highlighted the pivotal role of the complement system in myopia and other ocular conditions, emphasizing its central involvement in ocular inflammation and tissue remodeling. In myopia, complement activation may drive pathological axial elongation by fostering chronic ocular inflammation and extracellular matrix remodeling. Moreover, aberrant complement activity has been linked to genetic predisposition to myopia and the progression of complications associated with HM. However, the question of whether complement overactivation is a primary instigator of myopic changes or a secondary reaction to tissue stress remains unresolved. Future research should aim to unravel the molecular mechanisms underlying the interplay between complement pathways and structural remodeling in myopic eyes. Although current complement-targeted therapies are mainly applied in AMD, their potential in myopia has not yet been tested. Precise modulation of complement activity may ultimately provide new, personalized strategies for myopia prevention and management.

Footnotes

Acknowledgements

We thank all colleagues who provided valuable suggestions during the preparation of this article.

ORCID iD

Mengdi Zhang

Authors’ contributions

WJQ, JG, AQC, YZ, and SQW consulted previous relevant publications. MZ conceived and completed the manuscript with the assistance of YM. All authors had discussed and approved the final manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (Nos. 82274586, 81674031, and 82474581). Sichuan Administration of Traditional Chinese Medicine (2024YFFK0149).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

No datasets were generated or analyzed for this narrative review. All data cited are from publicly available published sources.

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