Abstract
Sepsis is a potentially life-threatening, pathological condition caused by a dysregulated host response to infection. Pathologically, systemic inflammation can initiate coagulation activation, leading to organ dysfunction, and ultimately to multiple organ failure and septic death. The inflammasomes are cytosolic multiprotein signaling complexes that control the host response to diverse pathogen-associated molecular patterns (PAMPs) from microorganisms as well as damage-associated molecular patterns (DAMPs) from dead or dying host cells. Recent studies highlight that the activation of canonical and non-canonical inflammasomes not only mediate the maturation and secretion of interleukin-1 (IL1) family cytokines, but also trigger the release of coagulation factor III, tissue factor (F3, best known as TF) in activated macrophages and monocytes. These emerging functions of inflammasomes in immunocoagulation are further positively regulated by stimulator of interferon response cGAMP interactor 1 (STING1, also known as STING or TMEM173, a hub of the innate immune signaling network) and high mobility group box 1 (HMGB1, a nuclear DAMP). This mini-review will discuss the regulation and function of inflammasome-dependent coagulation activation in sepsis.
Highlights
Sepsis is a challenging clinical syndrome characterized by life-threatening organ dysfunction or failure due to the dysregulated host immune response to pathogen infection, including bacteria, viruses, and fungi [1]
Inflammasomes are multiprotein intracellular complexes that detect the components of microorganisms [namely pathogen-associated molecular patterns (PAMPs)] and endogenous danger signals released by injured cells [namely damage-associated molecular patterns (DAMPs)] using various pattern recognition receptors (PRRs) [5]
Some DAMPs, such as cellfree DNA, histones, heat shock proteins, and high mobility group box 1 protein (HMGB1) [51, 52], have been reported to induce coagulopathy in sepsis by furtherly augmenting systemic inflammation [53] or impairing the activation of anticoagulants [54]. These DAMPs may be released from damaged cells due to apoptosis, necroptosis, or pyroptosis, but the contribution of cell death to coagulation in sepsis is contextdependent
Summary
Sepsis is a challenging clinical syndrome characterized by life-threatening organ dysfunction or failure due to the dysregulated host immune response to pathogen infection, including bacteria, viruses, and fungi [1]. Genetic depletion of core components of inflammasomes, such as Nlrp, Casp, Casp, and gasdermin D (Gsdmd), protects against septic shock [9,10,11,12,13,14,15] or lethal endotoxemia [7] in mice, turning them into a promising target for treatment of sepsis. In this mini-review, we introduce the types and activation of inflammasomes, discuss their roles in coagulation and thrombosis, and highlight their implications in sepsis
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