p204 Is Required for Canonical Lipopolysaccharide-induced TLR4 Signaling in Mice

p204, a murine member of an interferon-inducible p200 family, was reported to recognize intracellular viral and bacterial DNAs, however, its role in the innate immunity in vivo remains unknown due to the lack of p204-deficient animal models. In this study we first generated the p204−/− mice. Unexpectedly, p204 deficiency led to significant defect in extracellular LPS signaling in macrophages, as demonstrated by dramatic reductions of LPS-mediated IFN-β and pro-inflammatory cytokines. The serum levels of IFN-β and pro-inflammatory cytokines were also significantly reduced in p204−/− mice following LPS challenge. In addition, p204−/− mice were resistant to LPS-induced shock. LPS-activated NF-ĸB and IRF-3 pathways were all defective in p204-deficient macrophages. p204 binds to TLR4 through its Pyrin domain, and it is required for the dimerization of TLR4 following LPS-challenge. Collectively, p204 is a critical component of canonical LPS-TLR4 signaling pathway, and these studies also suggest that p204 could be a potential target to prevent and treat inflammatory and infectious diseases. •p204 deficiency leads to significant defect in extracellular LPS signaling in macrophages.•Serum levels of IFN-β and pro-inflammatory cytokines were also significantly reduced in p204-/- mice following LPS challenge.•p204-/- mice were resistant to LPS-induced shock.•p204 binds to TLR4 through its Pyrin domain, and it is required for the dimerization of TLR4 following LPS-challenge. Effective anti-pathogenic responses, including production of type I IFNs and inflammatory response, are critical for host defense. p200 family members, including IFI16 and AIM2, have been reported to function as the sensors of pathogen components. However, investigation of their roles has largely focused on intracellular pathogen components, independent of extracellular pathogen receptors, such as TLRs. Here, we provide unexpected evidences demonstrating that p204, a murine counterpart of human IFI16, is required for extracellular but not intracellular LPS signaling. These results provide not only evidence of functional crosstalk and cooperation between intracellular p204 and extracellular LPS through TLR4 pathways in macrophage-mediated innate immunity, but also new insights into the mechanisms underlying p200 family proteins mediated antiviral and antibacterial infections.