Subretinal macrophages produce classical complement activator C1q leading to the progression of focal retinal degeneration

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dc.contributor.authorJiao, Haihan Helen
dc.contributor.authorRutar, Matthew
dc.contributor.authorFernando, Nilisha
dc.contributor.authorYednock, Ted
dc.contributor.authorSankaranarayanan, Sethu
dc.contributor.authorAggio-Bruce, Riemke
dc.contributor.authorProvis, Jan
dc.contributor.authorNatoli, Riccardo
dc.date.accessioned2023-03-21T01:09:52Z
dc.date.available2023-03-21T01:09:52Z
dc.date.issued2018
dc.date.updated2022-01-16T07:17:49Z
dc.description.abstractBackground: The role of the alternative complement pathway and its mediation by retinal microglia and macrophages, is well-established in the pathogenesis of Age-Related Macular Degeneration (AMD). However, the contribution of the classical complement pathway towards the progression of retinal degenerations is not fully understood, including the role of complement component 1q (C1q) as a critical activator molecule of the classical pathway. Here, we investigated the contribution of C1q to progressive photoreceptor loss and neuroinflammation in retinal degenerations. Methods: Wild-type (WT), C1qa knockout (C1qa -/- ) and mice treated with a C1q inhibitor (ANX-M1; Annexon Biosciences), were exposed to photo-oxidative damage (PD) and were observed for progressive lesion development. Retinal function was assessed by electroretinography, followed by histological analyses to assess photoreceptor degeneration. Retinal inflammation was investigated through complement activation, macrophage recruitment and inflammasome expression using western blotting, qPCR and immunofluorescence. C1q was localised in human AMD donor retinas using immunohistochemistry. Results: PD mice had increased levels of C1qa which correlated with increasing photoreceptor cell death and macrophage recruitment. C1qa -/- mice did not show any differences in photoreceptor loss or inflammation at 7 days compared to WT, however at 14 days after the onset of damage, C1qa -/- retinas displayed less photoreceptor cell death, reduced microglia/macrophage recruitment to the photoreceptor lesion, and higher visual function. C1qa -/- mice displayed reduced inflammasome and IL-1β expression in microglia and macrophages in the degenerating retina. Retinal neutralisation of C1q, using an intravitreally-delivered anti-C1q antibody, reduced the progression of retinal degeneration following PD, while systemic delivery had no effect. Finally, retinal C1q was found to be expressed by subretinal microglia/macrophages located in the outer retina of early AMD donor eyes, and in mouse PD retinas. Conclusions: Our data implicate subretinal macrophages, C1q and the classical pathway in progressive retinal degeneration. We demonstrate a role of local C1q produced by microglia/macrophages as an instigator of inflammasome activation and inflammation. Crucially, we have shown that retinal C1q neutralisation during disease progression may slow retinal atrophy, providing a novel strategy for the treatment of complement-mediated retinal degenerations including AMD.en_AU
dc.description.sponsorshipThis research was supported by an Australian Government Research Training Program (RTP) Scholarshipen_AU
dc.format.mimetypeapplication/pdfen_AU
dc.identifier.issn1750-1326en_AU
dc.identifier.urihttp://hdl.handle.net/1885/287228
dc.language.isoen_AUen_AU
dc.provenanceThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.en_AU
dc.publisherBioMed Centralen_AU
dc.rights© 2018 The authorsen_AU
dc.rights.licenseCreative Commons Attribution licenceen_AU
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_AU
dc.sourceMolecular Neurodegenerationen_AU
dc.subjectMacrophagesen_AU
dc.subjectMicrogliaen_AU
dc.subjectComplement systemen_AU
dc.subjectClassical pathwayen_AU
dc.subjectC1qen_AU
dc.subjectInflammasomeen_AU
dc.subjectRetinal degenerationen_AU
dc.subjectPhoto-oxidative damageen_AU
dc.subjectInflammationen_AU
dc.subjectAge-related macular degenerationen_AU
dc.titleSubretinal macrophages produce classical complement activator C1q leading to the progression of focal retinal degenerationen_AU
dc.typeJournal articleen_AU
dcterms.accessRightsOpen Accessen_AU
local.bibliographicCitation.issue45en_AU
local.contributor.affiliationJiao, Haihan, College of Health and Medicine, ANUen_AU
local.contributor.affiliationRutar, Matthew, College of Health and Medicine, ANUen_AU
local.contributor.affiliationFernando, Nilisha, College of Health and Medicine, ANUen_AU
local.contributor.affiliationYednock, Ted, Annexon Biosciencesen_AU
local.contributor.affiliationSankaranarayanan, Sethu, Annexon Biosciencesen_AU
local.contributor.affiliationAggio-Bruce, Riemke, College of Health and Medicine, ANUen_AU
local.contributor.affiliationProvis, Jan, College of Health and Medicine, ANUen_AU
local.contributor.affiliationNatoli, Riccardo, College of Health and Medicine, ANUen_AU
local.contributor.authoremailu4861098@anu.edu.auen_AU
local.contributor.authoruidJiao, Haihan, u4861098en_AU
local.contributor.authoruidRutar, Matthew, u4125807en_AU
local.contributor.authoruidFernando, Nilisha, u4672578en_AU
local.contributor.authoruidAggio-Bruce, Riemke, u5333366en_AU
local.contributor.authoruidProvis, Jan, u4118802en_AU
local.contributor.authoruidNatoli, Riccardo, u4100537en_AU
local.description.notesImported from ARIESen_AU
local.identifier.absfor321204 - Vision scienceen_AU
local.identifier.ariespublicationa383154xPUB10614en_AU
local.identifier.citationvolume13en_AU
local.identifier.doi10.1186/s13024-018-0278-0en_AU
local.identifier.scopusID2-s2.0-85052151803
local.identifier.uidSubmittedBya383154en_AU
local.publisher.urlhttps://molecularneurodegeneration.biomedcentral.com/en_AU
local.type.statusPublished Versionen_AU

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