Smoothened-mediated signaling contributes to immune and non-immune functions of microglia

As the brain resident macrophages, microglia are endowed with functions ranging from key roles in cerebral development to mediation of innate immune responses. Diversity in microglia actions is consistent with the wide repertoire of their context-dependent states. However, mechanisms involved in the control of those states are still poorly understood. Here, we studied a small population of microglia expressing Smoothened, the well-known key transducer of the Hedgehog signaling. Our loss- and gain-of-function approaches uncover the so far unsuspected role of Smoothened intrinsic activity in triggering suitable innate immune responses to pathogens via the control of proper inflammatory and phagocytic states. This observation corelates with the detection of Smoothened upregulation in human fetal brains with congenital cytomegalovirus infection. Moreover, Smoothened contributes to the emergence of transient neonatal microglia by controlling its molecular signature. Altogether, our results shed new insight on improper microglial states related to impaired Smoothened activity and open therapeutic perspectives based on exogenous and non-canonical activation of this receptor.