More than Clearing the Clutter: The Imperative Role of Efferocytosis in Repair and Immune Reprogramming in the Damaged Nervous System

Abstract

Evolutionarily, the nervous system and immune system have been intertwined for hundreds of millions of years. In healthy conditions, these systems work diligently to maintain homeostasis and proper functioning. In summation, they keep our bodies moving, our organs operating, our minds thinking, and our bodies safe from foreign pathogenic invaders. However, in the event of a challenge to homeostasis, like a traumatic injury, both systems engage complex signaling cascades to degenerate parts of cells that can’t be saved, protect those that can, remove harmful debris, and regenerate and repair to again obtain homeostasis. A common system to study these complex response mechanisms is that of a peripheral nerve injury. My research over the past several years has been focused around fully understanding the complex immune-nerve communication and consequences that occur following peripheral nerve injury. The work herein keenly elaborates on the time course and content of the immune response after peripheral nerve crush injury. We show that granulocytes are the first to respond with infiltrating monocytes entering a few days later and finally dendritic cells about a week after injury. We however show little evidence of significant immune infiltration into dorsal root ganglia of the sciatic nerve and rather DRG-resident immune cell morphological changes. It is also demonstrated that mesenchymal progenitor cells are key in shaping the inflammatory milieu after injury. The requirement of Csf2 for conditioning-lesion-induced dorsal column axon regeneration is evidenced as well as its role in skewing the inflammatory response. The dynamicity of the immune non-immune responses to nerve injury in wild-type an SARM1 knockout animals at multiple timepoints is compared and contrasted. Finally, we are the first group to show the occurrence of efferocytosis (the phagocytosis of apoptotic cells) in the injured nerve, identify a specific transcriptomic identity for macrophages engaged in this action, and investigate the anti-inflammatory signaling this process propagates.