Abstract:

Immune effector mechanisms play key roles in the progressive (secondary) neurodegenerative changes that follow spinal cord injury (SCI). In our recent paper, 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 that is generated by the proteolysis of complement factor 5 (C5)) peaking between 12 and 24 hours post-injury. Activation of the complement system normally forms the frontline of host defense to microbial challenges. It is now widely recognized, however, that the activation of complement can also modify disease course and/or disease 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 also ascribing positive roles to at least some components of the complement cascade in tissue regeneration and repair. In studying the role of C5a in SCI, we generated novel insights regarding how this particular complement activation product is involved in endogenous repair processes. Specifically, we showed that engagement of the primary receptor for C5a, C5aR1 (also known as C5aR or CD88), during the post-acute phase regulates injury-induced astrocyte proliferation. Here, we overview these newly identified mechanisms and also highlight a number of outstanding questions that remain to be addressed when considering the therapeutic targeting of C5a-C5aR1 axis for the treatment of central nervous system (CNS) injury.