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

• Smo is expressed in a restricted population of microglia during the postnatal life. • Proper immune defense requires intrinsic Smo activity in microglia. • Exogenous Smo activation mitigates the pro-inflammatory states of microglia. • Microglial Smo transduces signals in a Hedgehog and Gli-independent manner. • Smo contributes to the emergence of the PAM subset in the developing white matter. The brain resident macrophages, or microglia, display essential functions ranging from contributing to brain development to triggering innate immune responses. The different ways microglia operate reflect their varying context-dependent states. However, the mechanisms that control these states remain largely unknown. Here, we identified a small population of microglia that express Smoothened (Smo), the well-known key component of the Hedgehog signaling pathway. Our experiments involving both loss and gain of function, demonstrate that the intrinsic activity of microglial Smo is mostly associated with the effective initiation of appropriate innate immune responses to pathogens and the control of microglia phagocytic activities. Microglial Smo activity is also involved in the appearance of amoeboid microglia that transiently arise in the developing white matter during the perinatal period. Moreover, the exogenous and Hedgehog signaling-independent activation of microglial Smo counteracts the molecular cascades occurring in microglia under inflammatory conditions. All these data indicate previously unrecognized roles for the Smo receptor and could lead to further research to discover a new category of non-canonical Smo agonists that might specifically regulate microglial states.