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

Abstract Ventral horn microglia in the spinal cord proliferate after nerve injuries and migrate towards the cell bodies of injured motoneurons surrounding them. However, the significance of microglia enwrapping axotomized motoneurons has remained unclear. Moreover, some injured motoneurons degenerate while others regenerate. In mice spinal cords we found that each motoneuron fate associates with microglia of different activation profiles. Microglia surrounding degenerating motoneurons form cell clusters that fully envelop the cell body and express high TREM2 and large CD68 granules, with female microglia expressing higher levels. Microglia surrounding motoneurons undergoing regeneration remain individualized and also upregulate TREM2 and CD68, but to a lesser extent than microglia around degenerating motoneurons. 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 cell clusters around degenerating motoneurons. This effect is also larger in females. TREM2 absence did not prevent microglia clustering around degenerating motoneurons but prevented the loss of some small MNs. In addition, TREM2 depletion interfered with the retrograde cell body chromatolytic reaction that is characteristic of regenerating motoneurons and delayed muscle reinnervation. We conclude that within the same motor pools, TREM2 facilitates microglia removal of some degenerating motoneurons while it facilitates regeneration of other motoneurons. The signals that direct the 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 Statement Microglia frequently enwrap neurons undergoing cellular stress being one example the microglia reaction around motoneurons axotomized after nerve injuries. The significance of this microglia-neuron relationship is unclear. We found that microglia surrounding axotomized motoneurons upregulate TREM2, but with differences depending on whether microglia associated with regenerative or degenerative motoneurons. Loss-of-function experiments showed that TREM2 promotes removal of some degenerating motoneurons while facilitates the regeneration of others. We conclude that microglia TREM2 serves a dual function depending on the motoneuron health state. This knowledge is critical for designing future therapies that aim to improve motoneuron regeneration or preservation by altering TREM2 function.