Activation of inflammatory resolution programs as a new therapeutic approach to promote neuroprotection after SCI

Abstract

The inflammatory response plays an essential role in protecting the body after injury or invasion by microorganisms, such as bacteria and parasites. However, inflammation must be a highly regulated process, otherwise, it may lead to tissue damage or even to inflammatory disease. In the nervous system, inflammatory response exerts a crucial role in promoting axonal regeneration after injury, as has been consistently shown in several models of peripheral nerve injury. Nevertheless, after spinal cord injury, an inefficient control of the inflammatory response occurs, which results in exacerbated tissue damage (death neurons and axonal disruption), in inefficient clearance of degenerating myelin, and does not remit over time. Recent studies have highlighted the importance of anti-inflammatory cytokines and specialized proresolving lipid mediators in triggering inflammatory resolution. These molecules prevent excessive inflammation and promote removal of microbes and apoptotic cells, thereby expediting resolution and return to tissue homeostasis. The present thesis reveals that the failure of the spinal cord to resolve inflammation after lesion is due, in part, to the inappropriate production of anti-inflammatory cytokines and specialized lipid mediators. Interestingly, it shows that administration of the anti-inflammatory cytokine IL-4, or the specialized proresolving lipid mediator, Maresin1, enhances inflammatory resolution after spinal cord injury in mice and promotes functional recovery and neuroprotection. Unexpectedly, treatment with two other specialized proresolving lipid mediators, resolvin D1 and lipoxin A4, does not show such therapeutic effect. Therefore, the work presented here provides new insights into the mechanisms that hampers the resolution of the inflammatory response after spinal cord injury, and suggest that IL-4 or Maresin1 might be novel useful candidates for the treatment of traumatic lesions in the central nervous system, and to other neurological conditions where inflammation contributes to the course of the pathology.

Date of Award	22 Jul 2016
Original language	English
Supervisor	Ruben Lopez Vales (Director)