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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A null allele of\n                      <jats:italic>C3ar1<\/jats:italic>\n                      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\n                      <jats:italic>C3ar1<\/jats:italic>\n                      -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\n                      <jats:italic>C3ar1<\/jats:italic>\n                      on microglia gene expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Deficiency in\n                      <jats:italic>C3ar1<\/jats:italic>\n                      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\n                      <jats:italic>C3ar1<\/jats:italic>\n                      deficiency was then overcome by additional aging and ocular hypertensive injury. Microglia and other myeloid-derived cells were the primary cells identified that express\n                      <jats:italic>C3ar1<\/jats:italic>\n                      . In the absence of\n                      <jats:italic>C3ar1<\/jats:italic>\n                      , 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      C3AR1 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\n                      <jats:italic>C3ar1<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12974-020-02011-z","type":"journal-article","created":{"date-parts":[[2020,11,11]],"date-time":"2020-11-11T00:02:18Z","timestamp":1605052938000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Complement peptide C3a receptor 1 promotes optic nerve degeneration in DBA\/2J mice"],"prefix":"10.1186","volume":"17","author":[{"given":"Jeffrey M.","family":"Harder","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6194-8397","authenticated-orcid":false,"given":"Pete A.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine E.","family":"Braine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongtian S.","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jocelyn M.","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole E.","family":"Foxworth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon W. 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