C3- and CR3-dependent microglial clearance protects photoreceptors in retinitis pigmentosa
| Autor: | Wenxin Ma, Wai T. Wong, Sean M. Silverman, Lian Zhao, Xu Wang |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine genetic structures Immunology Macrophage-1 Antigen Apoptosis Mice Transgenic Biology Retina Article Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Degenerative disease Phagocytosis Retinitis pigmentosa medicine Animals Humans Immunology and Allergy RNA Messenger Complement Activation Research Articles Microglia Neurodegeneration Neurotoxicity Retinal Complement C3 medicine.disease eye diseases Cell biology Complement system Mice Inbred C57BL Disease Models Animal 030104 developmental biology medicine.anatomical_structure chemistry Female sense organs Retinitis Pigmentosa 030217 neurology & neurosurgery Photoreceptor Cells Vertebrate Signal Transduction |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| DOI: | 10.1084/jem.20190009 |
| Popis: | Silverman et al. demonstrate that complement activation features prominently in retinitis pigmentosa in close association with activated microglia. This response mediates adaptive neuroprotection for photoreceptors by facilitating a C3-CR3–dependent clearance of apoptotic photoreceptors by microglial phagocytosis. 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. |
| Databáze: | OpenAIRE |
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