Spinal cord injury (SCI) produces chronic, pro-inflammatory macrophage activation that impairs recovery. 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 (cPLA2) in myelin-mediated potentiation of pro-inflammatory macrophage activation. We hypothesized that cPLA2 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 cPLA2 activation and intracellular accumulation of lipid-rich myelin debris in macrophages. In vitro, we utilized bone marrow-derived macrophages to determine myelin’s effects across a spectrum of activation states. We observed phenotype-specific responses with myelin potentiating only pro-inflammatory (LPS + INF-γ; 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 (cPLA2 inhibitor) blocked myelin’s detrimental effects. Collectively, we provide novel spatiotemporal evidence that myelin and cPLA2 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.
Digital Object Identifier (DOI)
National Institute of Neurological disorders and Stroke (NINDS) R01NS091582, NINDS T32 NS077889, and NINDS F31 NS105443.
The datasets analyzed during the current study are available from the corresponding author upon request. In vivo data will be made available through the Open Data Commons for Spinal Cord Injury (ODC-SCI: https://scicrunch.org/odc-sci).
Kopper, Timothy J.; Zhang, Bei; Bailey, William M.; Bethel, Kara E.; and Gensel, John C., "The Effects of Myelin on Macrophage Activation Are Phenotypic Specific via cPLA2 in the Context of Spinal Cord Injury Inflammation" (2021). Physiology Faculty Publications. 170.
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