Myelin as an inflammatory mediator: Myelin interactions with complement, macrophages, and microglia in spinal cord injury

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Excerpt

Spinal cord injury (SCI) triggers a complex cross talk between resident cells of the central nervous system (CNS) and infiltrating immune cells. These neuroimmune interactions can mediate recovery but also inhibit regeneration. Activated macrophages, consisting of resident microglia and recruited monocytes, contribute to this dichotomous response. Indeed, macrophages facilitate repair by increasing axon growth, stem cell differentiation, and revascularization. However, macrophages can also contribute to pathology through reactive oxygen species (ROS), neurotoxin, and proinflammatory cytokine release, as well as by causing axon retraction and dieback. The extent to which macrophages are polarized toward reparative (also called M2 or alternative) or pathological (also called M1 or proinflammatory) phenotypes depends in large part on the stimuli present in the injured spinal cord.
While numerous studies have examined how macrophage activation states affect recovery after SCI (for a review see Gensel & Zhang, 2015), less is understood about how the lesion environment contributes to macrophage polarization. It is well established that myelin debris generated after SCI inhibits axonal regeneration and remyelination (McKerracher et al., 1994); however, myelin can also act as an inflammatory stimulus (Kroner et al., 2014; Wang et al., 2015; Williams, Ulvestad, Waage, Antel, & McLaurin, 1994). Lipid‐laden myelin debris is taken up and processed by inflammatory cells including neutrophils and macrophages. Myelin then becomes highly concentrated in these phagocytes, persisting in macrophages for weeks after SCI (Greenhalgh & David, 2014; Vargas & Barres, 2007; Wang et al., 2015). In addition, myelin initiates complement‐mediated inflammatory pathways with downstream effects on macrophage activation. This review focuses on the myelin–macrophage and complement neuroimmune interactions after SCI. Since myelin is ubiquitously present in the acute and chronically injured spinal cord, we will explore the mechanisms of myelin debris clearance and its downstream inflammatory effects.

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