Regulation of innate immune responses in the central nervous system

Innate immune responses in the central nervous system must be tightly regulated as unrestrained activation generates a chronic inflammatory environment that can contribute to neurodegeneration and autoimmunity. Microglia express a wide variety of receptors of the innate immune system and are competent responders to danger. Toll-like receptor-, NOD-like receptor- and RIG1-like receptor-mediated activation of microglia leads to the production of pro-inflammatory cytokines and to the upregulation of molecules implicated in activation of the adaptive immune system. Activated microglia are a characteristic feature of many neuroinflammatory disorders and they represent an attractive therapeutic target. This review describes the mechanisms that are at play to restrain microglia activation under homeostatic conditions, such as CD172a, CD200R, SIGIRR and TREM2-mediated signaling, as well as dynamic inhibitory mechanisms that are at play during inflammatory conditions, such as adenosine receptor-mediated signaling. In addition, intracellular activating and inhibitory signaling cascades are summarized in detail and their therapeutic potential is analyzed.