Innate immune signaling and immunothrombosis: New insights and therapeutic opportunities

Abstract

Activation of the coagulation cascade is a critical, evolutionarily conserved mechanism that maintains hemostasis by rapidly forming blood clots in response to blood-borne infections and damaged blood vessels. Coagulation is a key component of innate immunity since it prevents bacterial dissemination and can provoke inflammation. The term immunothrombosis describes the process by which the innate immune response drives aberrant coagulation, which can result in a lethal condition termed disseminated intravascular coagulation, often seen in sepsis. In this review, we describe the recently uncovered molecular mechanisms underlying inflammasome- and STING-driven immunothrombosis induced by bacterial and viral infections, culminating in tissue factor (TF) activation and release. Current anticoagulant therapeutics, while effective, are associated with a life-threatening bleeding risk, requiring the urgent development of new treatments. Targeting immunothrombosis may provide a safer option. Thus, we highlight preclinical tools which target TF and/or block canonical (NLRP3) or noncanonical (caspase-11) inflammasome activation as well as STING-driven TF release and discuss clinically approved drugs which block key immunothrombotic processes and, therefore, may be redeployed as safer anticoagulants.

Keywords: STING; coagulation; immunothrombosis; inflammasomes; tissue factor.

Figure 1

Two major pathways of coagulation converge during hemostasis to form a blood clot. The original “waterfall” model of the coagulation cascade comprises the intrinsic and extrinsic pathways which converge into a common pathway to generate thrombin and form a fibrin clot. The intrinsic pathway primarily contributes to pathological clot formation and is activated when FXII encounters blood‐borne, negatively charged surfaces such as RNA, DNA, and components of atherosclerotic plaques. The extrinsic pathway is activated when subvascular TF is exposed to plasma, or released into the bloodstream via innate immune cell pyroptosis, where TF forms a cell‐surface complex with FVIIa. The intrinsic and extrinsic pathways combine to activate FX, which drives thrombin generation and ultimately blood clot formation. Endogenous inhibitors of the coagulation cascade include TFPI, activated protein C, and antithrombin.

Figure 2

Inflammasome‐ and STING‐mediated TF release drives thrombosis. Detection of a diverse range of microbes (such as viruses and Gram‐negative and Gram‐positive bacteria) by PRRs triggers innate immune signalling cascades which converge to activate IRF3/7 and NF‐κB. IRF3/7 stimulates expression of type I IFNs. This leads to IFN‐β release, which acts via the JAK‐STAT signalling complex to drive transcription of hundreds of ISGs including caspase‐11. Activation of STING can also drive this process. Caspase‐11 is then cleaved and activated upon recognition of cytosolic LPS (which occurs via HMGB1 and RAGE), triggering cleavage and activation of GSDMD, resulting in pyroptosis. GSDMD cleavage can also be triggered by caspase‐1 or caspase‐8 activation. Simultaneously, TF is induced by NF‐κB, before TF is post‐translationally activated, in a process termed decryption. Procoagulant TF is then released through the pyroptotic pores to drive thrombosis, which can result in thromboinflammation, sepsis, and disseminated intravascular coagulation. These signalling cascades have been shown to be blocked by a number of immunomodulatory compounds including DMF, heparin, STING inhibitors (C‐176, C‐178, H‐151), JAK inhibitors (Baricitinib, Ruxolitinib, Tofacitinib), and NLRP3 inflammasome inhibitors (4‐OI, Itaconate, MCC950). Thus, innate immune signalling can trigger TF‐mediated thrombosis via activation of the inflammasome and STING.