ZBP1 promotes inflammatory responses downstream of TLR3/TLR4 via timely delivery of RIPK1 to TRIF

Abstract

Significance While ZBP1 is well documented to drive cell death in response to viruses, its role in the context of Toll-like receptor (TLR)–mediated immune activation remains less defined. Here, we show that ZBP1 promotes inflammation in response to bacterial lipopolysaccharide (LPS) or double-stranded RNA (dsRNA). In a dose dependent manner, ZBP1 promotes the recruitment of RIPK1 to the TLR3/4 adaptor TRIF, activating downstream inflammatory signaling. ZBP1 plays a crucial role in TRIF-dependent responses in vivo , as Zbp1 −/− mice exhibited resistance to LPS-induced hypothermia and attenuated inflammatory responses to dsRNA. Our findings suggest that ZBP1 plays a synergistic role in the immune response by driving inflammation downstream of TLRs in response to bacterial and viral components.