Abstract
BackgroundThe risk of glaucoma increases significantly with age and exposure to elevated intraocular pressure, two factors linked with neuroinflammation. The complement cascade is a complex immune process with many bioactive end-products, including mediators of inflammation. Complement cascade activation has been shown in glaucoma patients and models of glaucoma. However, the function of complement-mediated inflammation in glaucoma is largely untested. Here, the complement peptide C3a receptor 1 was genetically disrupted in DBA/2J mice, an ocular hypertensive model of glaucoma, to test its contribution to neurodegeneration.MethodsA null allele of C3ar1 was backcrossed into DBA/2J mice. Development of iris disease, ocular hypertension, optic nerve degeneration, retinal ganglion cell activity, loss of RGCs, and myeloid cell infiltration in C3ar1-deficient and sufficient DBA/2J mice were compared across multiple ages. RNA sequencing was performed on microglia from primary culture to determine global effects of C3ar1 on microglia gene expression.ResultsDeficiency in C3ar1 lowered the risk of degeneration in ocular hypertensive mice without affecting intraocular pressure elevation at 10.5 months of age. Differences were found in the percentage of mice affected, but not in individual characteristics of disease progression. The protective effect of C3ar1 deficiency was then overcome by additional aging and ocular hypertensive injury. Microglia and other myeloid-derived cells were the primary cells identified that express C3ar1. In the absence of C3ar1, microglial expression of genes associated with neuroinflammation and other immune functions were differentially expressed compared to WT. A network analysis of these data suggested that the IL10 signaling pathway is a major interaction partner of C3AR1 signaling in microglia.ConclusionsC3AR1 was identified as a damaging neuroinflammatory factor. These data help suggest complement activation causes glaucomatous neurodegeneration through multiple mechanisms, including inflammation. Microglia and infiltrating myeloid cells expressed high levels of C3ar1 and are the primary candidates to mediate its effects. C3AR1 appeared to be a major regulator of microglia reactivity and neuroinflammatory function due to its interaction with IL10 signaling and other immune related pathways. Targeting myeloid-derived cells and C3AR1 signaling with therapies is expected to add to or improve neuroprotective therapeutic strategies.
Highlights
Glaucoma is a common disease that damages the optic nerve and impairs vision [1]
C3a receptor (C3ar1)-deficient DBA/2J mice developed elevated intraocular pressure similar to C3ar1 sufficient mice DBA/2J mice inherit a depigmenting iris disease that leads to high IOP and glaucoma [33, 39]
To determine whether C3ar1 deficiency affected iris disease or IOP elevation, eyes of C3ar1−/− mice and their C3ar1+/+ littermates were examined regularly beginning at 6 months of age
Summary
Glaucoma is a common disease that damages the optic nerve and impairs vision [1]. Risk for glaucoma is greatly increased after middle age and by exposure to elevated intraocular pressure (IOP). Elevated IOP and aging are associated with neuroinflammation, yet it remains unclear when and how neuroinflammation becomes damaging in glaucoma and how to intervene [2, 3]. These questions underlie a need to develop a comprehensive understanding of inflammatory processes in glaucoma. The final product of the complement cascade, the membrane attack complex (MAC), has been identified in optic nerve tissue from ocular hypertensive patients. This suggests full activation of the complement cascade has occurred, including multiple steps that promote neuroinflammation. The complement peptide C3a receptor 1 was genetically disrupted in DBA/2J mice, an ocular hypertensive model of glaucoma, to test its contribution to neurodegeneration
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