Dual Role of Microglial TREM2 in Neuronal Degeneration and Regeneration After Axotomy

After nerve injuries, spinal cord microglia proliferate and migrate towards injured motoneurons surrounding their cell bodies. The significance of microglia enwrapping motoneurons remains unclear. Within the same motor pools some motoneurons degenerate while others regenerate, and each associate with different microglia phenotypes. Microglia surrounding degenerating motoneurons form tight cell clusters (“death clusters”) that fully envelop the cell body and express high TREM2 and large CD68 granules, suggesting a macrophagocyte phenotype for motoneuron removal. Microglia surrounding motoneurons undergoing regeneration remain individualized and also upregulate TREM2 and CD68, although to a lower extent, and CD68 granules are smaller. Microglia on regenerating motoneurons extend processes that scan the cell body surface through sweeping motions, likely sampling contents and endocytosing motoneuron-derived material through microphagocytosis. Removal of TREM2, either globally throughout development or specifically in microglia prior to nerve injuries, reduces p-SYK signaling and CD68 expression in all activated microglia, but particularly inside death clusters. There are also pronounce sex differences: CD68 upregulation and downregulation was more significant in females. TREM2 depletion on microglia over regenerating motoneurons prevented the cell body swelling (in both sexes) characteristic of the chromatolytic reaction at the start of regeneration. This correlated with muscle reinnervation delays. We conclude that within the same motor pools, TREM2 facilitates microglia removal of degenerating motoneurons while it facilitates regeneration on other motoneurons. The signals that direct these different microglia phenotypes over degenerating and regenerating motoneurons, as well as the mechanisms that induce degeneration in some motoneurons while most others regenerate, remain to be investigated.