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

Spinal cord ventral horn microglia proliferate after nerve injuries and migrate toward cell bodies of injured motoneurons (MNs) enwrapping them. The significance of this microglia reaction has remained unclear. Moreover, some injured MNs degenerate while others regenerate. In mice spinal cords, we found that each MN fate associates with microglia of different activation profiles. Microglia surrounding degenerating MNs form cell clusters that fully envelop the cell body and express high triggering receptor expressed on myeloid cells 2 (TREM2) and large CD68 granules, with female microglia expressing higher levels. Microglia surrounding MNs undergoing regeneration remain individualized and also upregulate TREM2 and CD68 but to a lesser extent. Removal of TREM2, either globally throughout development or specifically in microglia prior to nerve injuries, reduces phosphorylated spleen tyrosine kinase signaling and CD68 expression in all activated microglia but more so inside microglia forming tight cell clusters around degenerating MNs. This effect is also larger in females. TREM2 absence did not prevent microglia clustering around degenerating MNs but prevented the loss of some small MNs. In addition, TREM2 depletion interfered with the retrograde cell body chromatolytic reaction characteristic of regenerating MNs and delayed muscle reinnervation. We conclude that within the same motor pools, TREM2 facilitates microglia removal of some degenerating MNs, while it facilitates regeneration of others. The signals that direct the development of these different microglia phenotypes over degenerating and regenerating MNs, as well as the mechanisms that induce degeneration in some MNs while most others regenerate, remain to be investigated.