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The mechanisms driving this chronic inflammation are not well understood. Here, we detail the effects of myelin debris on macrophage physiology and demonstrate a novel, activation state-dependent role for cytosolic phospholipase-A2 (cPLA\n                    <jats:sub>2<\/jats:sub>\n                    ) in myelin-mediated potentiation of pro-inflammatory macrophage activation. We hypothesized that cPLA\n                    <jats:sub>2<\/jats:sub>\n                    and myelin debris are key mediators of persistent pro-inflammatory macrophage responses after SCI. To test this, we examined spinal cord tissue 28-days after thoracic contusion SCI in 3-month-old female mice and observed both cPLA\n                    <jats:sub>2<\/jats:sub>\n                    activation and intracellular accumulation of lipid-rich myelin debris in macrophages. In vitro\n                    <jats:italic>,<\/jats:italic>\n                    we utilized bone marrow-derived macrophages to determine myelin\u2019s effects across a spectrum of activation states. We observed phenotype-specific responses with myelin potentiating only pro-inflammatory (LPS\u2009+\u2009INF-\u03b3; M1) macrophage activation, whereas myelin did not induce pro-inflammatory responses in unstimulated or anti-inflammatory (IL-4; M2) macrophages. Specifically, myelin increased levels of pro-inflammatory cytokines, reactive oxygen species, and nitric oxide production in M1 macrophages as well as M1-mediated neurotoxicity. PACOCF3 (cPLA\n                    <jats:sub>2<\/jats:sub>\n                    inhibitor) blocked myelin\u2019s detrimental effects. Collectively, we provide novel spatiotemporal evidence that myelin and cPLA\n                    <jats:sub>2<\/jats:sub>\n                    play an important role in the pathophysiology of SCI inflammation and the phenotype-specific response to myelin implicate diverse roles of myelin in neuroinflammatory conditions.\n                  <\/jats:p>","DOI":"10.1038\/s41598-021-85863-6","type":"journal-article","created":{"date-parts":[[2021,3,18]],"date-time":"2021-03-18T12:47:41Z","timestamp":1616071661000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["The effects of myelin on macrophage activation are phenotypic specific via cPLA2 in the context of spinal cord injury inflammation"],"prefix":"10.1038","volume":"11","author":[{"given":"Timothy J.","family":"Kopper","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William M.","family":"Bailey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kara E.","family":"Bethel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Gensel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,18]]},"reference":[{"key":"85863_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.brainres.2014.12.045","volume":"1619","author":"JC Gensel","year":"2015","unstructured":"Gensel, J. 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