Targeting acute inflammation to complement spinal cord repair

Immune effector mechanisms play key roles in the progressive (secondary) neurodegenerative changes that follow spinal cord injury (SCI). In our recent paper (Brennan et al., 2015), we showed that the inflammatory response to SCI includes rapid and robust activation of the innate immune complement system, with tissue levels of complement component 5a (C5a – an activation product generated by the proteolysis of complement factor 5 (C5)) peaking 12 to 24 hours post-injury. Complement system activation normally forms the front-line of host defense to microbial challenges. It is now widely recognized, however, that the activation of complement can also modify disease course and/or outcomes in sterile inflammatory conditions, including those that affect the nervous system like SCI. Complement activation in such conditions has been mostly thought of as detrimental, but several reports have emerged in recent years ascribing positive roles in tissue regeneration and repair to at least some components of the complement cascade (e.g., Haynes et al., 2013). In studying the role of C5a in SCI, we generated novel insights regarding how this particular complement activation product also appears involved in endogenous repair processes. Specifically, we showed that engagement of the primary receptor for C5a, C5aR1 (also known as C5aR or CD88), regulates astrocyte proliferation during the post-acute phase of SCI (Brennan et al., 2015). Here, we overview these newly identified mechanisms and highlight outstanding questions that remain to be addressed when considering therapeutic targeting of the C5a-C5aR1 axis to treat central nervous system (CNS) injury. Breakdown of the blood-spinal cord barrier (BSB) following a neurotraumatic event permits the entry of circulating blood serum proteins, including complement factors, into the injured parenchyma. Permeability to larger macromole-cules such as the parent protein of C5a, i.e., C5 (~180 kDa), is likely restricted to the first hours to days after SCI (e.g., Lee et al., 2014), but may be longer for smaller molecules like C5a (12–14.5 kDa). Although the liver is a major source of complement proteins in the body, many of these can also be synthesized by cells that are intrinsic to the CNS. The pathophysiological role of the complement system in SCI is therefore not necessarily restricted to the (sub-) acute phase when the BSB is most compromised. Proteolytic cleavage (i.e., activation) of C5 following neu-rotrauma is a key event that is thought to contribute significantly to secondary neuroinflammatory pathology via 1) activation of the terminal pathway (which causes cell death …