Emerging mechanisms of immunocoagulation in sepsis and septic shock

Sepsis is a life-threatening organ dysfunction caused by the abnormal host response to infection, including to the new virus SARS-CoV-2 responsible for the COVID-19 ongoing pandemic in humans. The crosstalk between a mounting immune dysfunction and abnormal blood coagulation is the basic event favoring sepsis complications and multiple organ failure in humans and should be strategically targeted for therapeutic purposes. GSDMD is an effector of pyroptosis induced by canonical and non-canonical inflammasomes and plays an emerging role in the regulation of coagulation tissue factor F3 release and activation in human or mouse macrophages and monocytes. HMGB1-dependent LPS uptake by AGER or STING1-mediated cytosolic Ca2+ influx by ITPR1 promotes CASP1-, CASP11-, or CASP8-induced GSDMD activation and subsequent F3 release by human or mouse macrophages and monocytes. Extracellular SQSTM1 is a previously unrecognized mediator of septic death in mice that acts to activate the insulin receptor pathway in human or mouse macrophages and monocytes. Globally and/or conditionally deleting Casp1, Casp11, Gsdmd, Hmgb1, Ager, Sting1, Sqstm1, or Insr can prevent inflammation, coagulopathy, multiple organ failure, and lethality in mouse models of bacterial sepsis. Sepsis and septic shock driven by microbial infections are still among the most challenging health problems, causing 11 million deaths worldwide every year. How does the host’s response to pathogen infections effectively restore homeostasis instead of precipitating pathogenic and potentially fatal feedforward reactions? Recently, there have been significant new advances in our understanding of the interface between mammalian immunity and coagulation (‘immunocoagulation’) and its impact on sepsis. In particular, the release and activation of F3 (the main initiator of coagulation) from and on myeloid or epithelial cells is facilitated by activating inflammasomes and consequent gasdermin D (GSDMD)-mediated pyroptosis, coupled to signaling via high mobility group box 1 (HMGB1), stimulator of interferon response CGAMP interactor 1 (STING1), or sequestosome 1 (SQSTM1). Pharmacological modulation of the immunocoagulation pathways emerge as novel and potential therapeutic strategies for sepsis. Sepsis and septic shock driven by microbial infections are still among the most challenging health problems, causing 11 million deaths worldwide every year. How does the host’s response to pathogen infections effectively restore homeostasis instead of precipitating pathogenic and potentially fatal feedforward reactions? Recently, there have been significant new advances in our understanding of the interface between mammalian immunity and coagulation (‘immunocoagulation’) and its impact on sepsis. In particular, the release and activation of F3 (the main initiator of coagulation) from and on myeloid or epithelial cells is facilitated by activating inflammasomes and consequent gasdermin D (GSDMD)-mediated pyroptosis, coupled to signaling via high mobility group box 1 (HMGB1), stimulator of interferon response CGAMP interactor 1 (STING1), or sequestosome 1 (SQSTM1). Pharmacological modulation of the immunocoagulation pathways emerge as novel and potential therapeutic strategies for sepsis. transmembrane receptor of the immunoglobulin superfamily that mediates inflammation by recognizing various ligands. a non-heme iron-containing enzyme of the lipoxygenase family, which mediates lipid peroxidation. Ca2+-dependent phospholipid scramblase, which mediates phosphatidylserine exposure during cell death. unusual susceptibility to bleeding, mostly due to a defect in the coagulation system. severe immune response in which the body releases too many cytokines into the circulatory system. host or environmental molecules that can trigger an immune response when released. pathological condition that can cause abnormal blood clotting throughout the body’s blood vessels. cell surface adhesion protein mediating plasma membrane rupture during lytic cell death. structural components or products of pathogens that can trigger innate immune cell activation. receptors that can recognize PAMPs, DAMPs, or stressors. lytic proinflammatory type of cell death that is mainly initiated through caspases (e.g., CASP1, CASP4/5/11, CASP8, or CASP3) and mediated through gasdermins (e.g., GSDMD or GSDME). abnormal retention of fat or lipids within cells or organs.