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

After nerve injuries ventral horn spinal cord microglia proliferate, migrate towards injured motoneurons cell bodies and surround them. The significance of microglia enwrapping axotomized motoneurons remains unclear. Moreover, some motoneurons degenerate while others regenerate. We found that each motoneurons fate is associated with a different microglia activation profile. Microglia surrounding degenerating motoneurons form tight cell clusters that fully envelop the cell body and express high TREM2 and large CD68 granules (with some sex differences), suggesting macrophagocytic activities for motoneuron removal. Microglia surrounding motoneurons undergoing regeneration remain individualized and also upregulate TREM2 and CD68, but to a lower extent than microglia around degenerating motoneurons and lack large CD68 granules. 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 more so inside microglia forming tight clusters around degenerating motoneurons. This effect is larger in females. TREM2 absence did not, however, prevent formation of microglia clusters around degenerating motoneurons. TREM2 depletion on microglia over regenerating motoneurons prevented the cell body swelling (similarly in both sexes) characteristic of the chromatolytic reaction at the start of regeneration and delayed muscle reinnervation. We conclude that within the same motor pools, TREM2 facilitates microglia removal of degenerating motoneurons while it facilitates regeneration of other motoneurons. The signals that direct development of 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. Significance StatementMicroglia frequently enwrap neurons undergoing cellular stress. One example is motoneurons axotomized after nerve injuries, but the significance of this microglia-neuron relationship is unclear. We found that microglia surrounding axotomized motoneurons upregulate TREM2, but with differences in whether microglia surround regenerative or degenerative motoneurons. Loss-of-function experiments showed that TREM2 is involved in promoting removal of degenerating motoneurons while facilitating regeneration of surviving motoneurons. We conclude that microglia TREM2 serves a dual function depending on the motoneuron health state. This knowledge is critical to design future therapies that seek to improve motoneuron regeneration or preservation by altering TREM2 function.