Reverse Signaling of Tumor Necrosis Factor Superfamily Proteins in Macrophages and Microglia: Superfamily Portrait in the Neuroimmune Interface

The tumor necrosis factor (TNF) superfamily (TNFSF) is a protein superfamily of type II transmembrane proteins commonly containing the TNF homology domain. The superfamily contains more than 20 protein members, which can be released from the cell membrane by proteolytic cleavage. Members of the TNFSF function as cytokines and regulate diverse biological processes, including immune responses, proliferation, differentiation, apoptosis, and embryogenesis, by binding to TNFSF receptors. Many TNFSF proteins are also known to be responsible for the regulation of innate immunity and inflammation. Both receptor-mediated forward signaling and ligand-mediated reverse signaling play important roles in these processes. In this review, we discuss the functional expression and roles of various reverse signaling molecules and pathways of TNFSF members in macrophages and microglia in the central nervous system (CNS). A thorough understanding of the roles of TNFSF ligands and receptors in the activation of macrophages and microglia may improve the treatment of inflammatory diseases in the brain and periphery. In particular, TNFSF reverse signaling in microglia can be exploited to gain further insights into the functions of the neuroimmune interface in physiological and pathological processes in the CNS.