Regulation of Tumor Necrosis Factor-Induced Cell Death and Toll-Like Receptor-Mediated Activation of Macrophages by SPATA2

Abstract

Cell death and innate immunity are interconnected events for multicellular organisms to defend against pathogenic microbes and restrict tissue damage. Macrophages constitute an important population of innate immunity. Their survival and activation are critical for the local and systematic inflammation. Tumor necrosis factor (TNF) is an important pro-inflammatory factor and a major cause of cell death in vivo under pathological conditions. TNF can promote apoptosis, a hypoimmunogenic type of cell death that is preferentially triggered to restrict inflammation, or necroptosis, an immunogenic type of cell death that releases danger signals to the environment. These danger signals activate immune receptors such as toll-like receptors (TLRs). TLRs are the major family of receptors that sense extracellular pathogen- or damage-associated molecular patterns and elicit pro-inflammatory or antiviral responses. Here I present a thesis describing the mechanism and functions of a gene named Spata2 that plays a dual role in regulating TNF-induced cell death as well as TLR-mediated pro-inflammatory responses. TNF-induced necroptosis involves a receptor-binding Complex I that initiates pro-survival signaling, and an intracellular Complex IIb that activates a toxic membrane-permeabilizing protein to execute cell death. I show that Spata2 promotes the formation of complex IIb without affecting the pro-survival function of complex I. In addition, I describe that Spata2 inhibits the production of pro-inflammatory cytokines, such as TNF, IL-6, and IL-12p40, in response to the activation of TLRs. Interestingly, Spata2 has no affect on the core signaling pathway that activates canonical NF-κB and MAP kinases; instead, it modulates IRAK2-mediated mRNA degradation upon TLR activation. Mutant mice that are deficient for Spata2 show enhanced susceptibility to TNF-induced septic shock, consistent with the immunosuppressive function of Spata2.