Complement peptide C3a receptor 1 promotes optic nerve degeneration in DBA/2J mice
Jeffrey M Harder1, Pete A Williams1,2, Catherine E Braine1,3
1The Jackson Laboratory, Bar Harbor, ME, USA.
Journal of Neuroinflammation
|November 12, 2020
Summary
Targeting the C3a receptor 1 (C3AR1) pathway may protect against glaucoma. Disrupting C3AR1 in mice reduced neurodegeneration, suggesting it’s a key factor in this eye disease.
Area of Science:
- Ophthalmology
- Neuroscience
- Immunology
Background:
- Glaucoma risk increases with age and elevated intraocular pressure, both linked to neuroinflammation.
- The complement cascade, an immune process, is activated in glaucoma patients and models.
- The precise role of complement-mediated inflammation in glaucoma has been unclear.
Purpose of the Study:
- To investigate the contribution of the complement peptide C3a receptor 1 (C3AR1) to neurodegeneration in glaucoma.
- To genetically disrupt C3AR1 in DBA/2J mice, a model of ocular hypertensive glaucoma.
Main Methods:
- A null allele of C3ar1 was introduced into DBA/2J mice.
- Development of glaucoma-related pathologies (iris disease, ocular hypertension, optic nerve degeneration, RGC loss) was compared between C3ar1-deficient and sufficient mice.
- RNA sequencing analyzed gene expression in microglia to understand C3AR1's effects.
Main Results:
- C3ar1 deficiency reduced neurodegeneration risk in ocular hypertensive mice without altering intraocular pressure.
- Microglia and myeloid cells were identified as primary expressers of C3AR1.
- Absence of C3AR1 altered microglial gene expression related to neuroinflammation and immune function, notably involving the IL10 signaling pathway.
Conclusions:
- C3AR1 acts as a detrimental neuroinflammatory factor in glaucoma.
- Complement activation contributes to glaucomatous neurodegeneration via inflammation, with C3AR1 mediating effects through microglia and myeloid cells.
- Targeting C3AR1 and myeloid cells offers potential neuroprotective therapeutic strategies for glaucoma.
