Abstract
Receptor-interacting protein kinase 3 (RIPK3) is a key regulator of programmed cell death and inflammation during viral infection or sterile tissue injury. Whether and how bacterial infection also activates RIPK3-dependent immune responses remains poorly understood. Here we show that bacterial lipids (lipid IVa or lipid A) form a complex with high mobility group box 1 (HMGB1), released by activated immune cells or damaged tissue during bacterial infection, and that this complex triggers RIPK3- and TIR domain-containing adapter-inducing IFN-β (TRIF)-dependent immune responses. We found that these responses lead to macrophage death, interleukin (IL)-1α release, and IL-1β maturation. In an air-pouch inflammatory infiltration model, genetic deletion of Ripk3, Trif, or IL-1 receptor (Il-1R), or monoclonal antibody-mediated HMGB1 neutralization uniformly attenuated inflammatory responses induced by Gram-negative bacteria that release lipid IVa and lipid A. These findings uncover a previously unrecognized mechanism by which host factors and bacterial components work in concert to orchestrate immune responses.
Highlights
Receptor-interacting protein kinase 3 (RIPK3) is a key regulator of programmed cell death and inflammation during viral infection or sterile tissue injury
To investigate whether high mobility group box 1 (HMGB1) and bacterial lipids could work in concert to orchestrate immune responses, mouse peritoneal macrophages were stimulated with lipid A or lipid IVa in the absence or presence of highly purified recombinant HMGB1 protein
Our data shown that endogenous HMGB1 released from necrotic WT mouse embryonic fibroblasts (MEFs) enabled lipid IVa or lipid A to induce the release of IL-1␣ and IL-1, which was markedly inhibited by HMGB1 neutralizing monoclonal antibodies (Fig. 1E, Fig. S2)
Summary
High mobility group box 1 enables bacterial lipids to trigger receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis and apoptosis in mice. We show that bacterial lipids (lipid IVa or lipid A) form a complex with high mobility group box 1 (HMGB1), released by activated immune cells or damaged tissue during bacterial infection, and that this complex triggers RIPK3- and TIR domain-containing adapter-inducing IFN- (TRIF)-dependent immune responses. In an air-pouch inflammatory infiltration model, genetic deletion of Ripk, Trif, or IL-1 receptor (Il-1R), or monoclonal antibody-mediated HMGB1 neutralization uniformly attenuated inflammatory responses induced by Gram-negative bacteria that release lipid IVa and lipid A These findings uncover a previously unrecognized mechanism by which host factors and bacterial components work in concert to orchestrate immune responses. In an air-pouch inflammatory infiltration model, the genetic deletion of Ripk, Trif, or Il-1R, or neutralizing HMGB1 attenuates the nonresolving inflammation induced by Gram-negative bacteria These findings uncover a previously unrecognized mechanism by which host factors and bacterial components work in concert to orchestrate RIPK3-dependent immune responses under pathophysiological conditions
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