Dataset Information

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

ABSTRACT: SignificanceWhile 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.

SUBMITTER: Muendlein HI

PROVIDER: S-EPMC9214535 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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

Muendlein Hayley I HI Connolly Wilson M WM Magri Zoie Z Jetton David D Smirnova Irina I Degterev Alexei A Balachandran Siddharth S Poltorak Alexander A

Proceedings of the National Academy of Sciences of the United States of America 20220606 24

ZBP1 is widely recognized as a mediator of cell death for its role in initiating necroptotic, apoptotic, and pyroptotic cell death pathways in response to diverse pathogenic infection. Herein, we characterize an unanticipated role for ZBP1 in promoting inflammatory responses to bacterial lipopolysaccharide (LPS) or double-stranded RNA (dsRNA). In response to both stimuli, ZBP1 promotes the timely delivery of RIPK1 to the Toll-like receptor (TLR)3/4 adaptor TRIF and M1-ubiquitination of RIPK1, wh ...[more]

PMID: 35666872

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Project description:Binge/moderate alcohol suppresses TLR4-MyD88 proinflammatory cytokines; however, alcohol's effects on TLR-TRIF signaling, especially after in vivo exposure in humans, are unclear. We performed a comparative analysis of the TLR4-MyD88, TLR4-TRIF, and TLR3-TRIF pathways in human monocytes following binge alcohol exposure. Mechanistic regulation of TLR-TRIF signaling by binge alcohol was evaluated by analyzing IRF3 and TBK1, upstream regulator protein phosphatase 1 (PP1), and immunoregulatory stress proteins HspA1A and XBP-1 in alcohol-treated human and mouse monocytes/macrophages. Two approaches for alcohol exposure were used: in vivo exposure of primary monocytes in binge alcohol-consuming human volunteers or in vitro exposure of human monocytes/murine macrophages to physiological alcohol concentrations (25-50 mM ethanol), followed by LPS (TLR4) or polyinosinic-polycytidylic acid (TLR3) stimulation ex vivo. In vivo and in vitro binge alcohol exposure significantly inhibited the TLR4-MyD88 cytokines TNF-α and IL-6, as well as the TLR4-TRIF cytokines/chemokines IFN-β, IP-10, and RANTES, in human monocytes, but not TLR3-TRIF-induced cytokines/chemokines, as detected by quantitative PCR and ELISA. Mechanistic analyses revealed TBK-1-independent inhibition of the TLR4-TRIF effector IRF3 in alcohol-treated macrophages. Although stress protein XBP-1, which is known to regulate IRF3-mediated IFN-β induction, was not affected by alcohol, HspA1A was induced by in vivo alcohol in human monocytes. Alcohol-induced HspA1A was required for inhibition of TLR4-MyD88 signaling but not TLR4-TRIF cytokines in macrophages. In contrast, inhibition of PP1 prevented alcohol-mediated TLR4-TRIF tolerance in macrophages. Collectively, our results demonstrate that in vivo and in vitro binge alcohol exposure in humans suppresses TLR4-MyD88 and TLR4-TRIF, but not TLR3-TRIF, responses. Whereas alcohol-mediated effects on the PP1-IRF3 axis inhibit the TLR4-TRIF pathway, HspA1A selectively suppresses the TLR4-MyD88 pathway in monocytes/macrophages.

Dataset Information

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

Publications

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

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