Abstract |
Complement activation has been implicated as contributing to neurodegeneration in retinal and brain pathologies, but its role in retinitis pigmentosa (RP), an inherited and largely incurable photoreceptor degenerative disease, is unclear. We found that multiple complement components were markedly up-regulated in retinas with human RP and the rd10 mouse model, coinciding spatiotemporally with photoreceptor degeneration, with increased C3 expression and activation localizing to activated retinal microglia. Genetic ablation of C3 accelerated structural and functional photoreceptor degeneration and altered retinal inflammatory gene expression. These phenotypes were recapitulated by genetic deletion of CR3, a microglia-expressed receptor for the C3 activation product iC3b, implicating C3-CR3 signaling as a regulator of microglia-photoreceptor interactions. Deficiency of C3 or CR3 decreased microglial phagocytosis of apoptotic photoreceptors and increased microglial neurotoxicity to photoreceptors, demonstrating a novel adaptive role for complement-mediated microglial clearance of apoptotic photoreceptors in RP. These homeostatic neuroinflammatory mechanisms are relevant to the design and interpretation of immunomodulatory therapeutic approaches to retinal degenerative disease.
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Authors | Sean M Silverman, Wenxin Ma, Xu Wang, Lian Zhao, Wai T Wong |
Journal | The Journal of experimental medicine
(J Exp Med)
Vol. 216
Issue 8
Pg. 1925-1943
(08 05 2019)
ISSN: 1540-9538 [Electronic] United States |
PMID | 31209071
(Publication Type: Journal Article, Research Support, N.I.H., Intramural)
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Copyright | This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply. |
Chemical References |
- Complement C3
- Macrophage-1 Antigen
- RNA, Messenger
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Topics |
- Animals
- Apoptosis
(genetics)
- Complement Activation
(immunology)
- Complement C3
(genetics, metabolism)
- Disease Models, Animal
- Female
- Humans
- Macrophage-1 Antigen
(genetics, metabolism)
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Microglia
(metabolism)
- Phagocytosis
(genetics)
- Photoreceptor Cells, Vertebrate
(immunology, metabolism)
- RNA, Messenger
(genetics)
- Retina
(pathology)
- Retinitis Pigmentosa
(immunology)
- Signal Transduction
(immunology)
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