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 lifethreatening 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.

Construction of Autophagy-Related Gene Classifier for Early Diagnosis, Prognosis and Predicting Immune Microenvironment Features in Sepsis by Machine Learning Algorithms

“… 28 Abnormal blood coagulation is the basic event eliciting sepsis complications and multiple organ failure in humans, thus it should be strategically targeted for therapeutic purposes. 29 In the current study, we found that the complement and coagulation cascades were mainly enriched in the ARG high-expression subtypes that are associated with unfavorable survival outcome. Hence, we speculated that eight ARGs of the ARG classifier may participate in complement and coagulation cascades to affect the progress of patients with sepsis.…”

Immunothrombosis: Molecular Aspects and New Therapeutic Perspectives

“…The presence of PAMPs and other dangerous molecular signals (DAMPs) activate caspases and induces pyroptosis and cellular death through gasdermins, which are the executors of inflammation and cell death. The so called non-canonical inflammasome activation is produced as a consequence of caspase-11 induction by LPS-associated gram-negative bacteria in different immune and nonimmune cells, including neutrophils, macrophages, and endothelial cells [ 17 ]. The caspase-11 activation promotes gasdermin D proteolysis, which provokes cell lysis named pyroptosis, which is a critical antibacterial defense mechanism that avoids pathogen dissemination [ 7 , 18 , 19 ].…”

“…Recent experimental and clinical studies have demonstrated that the canonical and non-canonical activation of the inflammasome are crucial for TF release by immune cells [ 17 ]. In this sense, several reports show that caspase-1 is present in human macrophages during sepsis.…”

“…Previously, in vitro studies demonstrated TF induction and decryption in response to different viruses, such as herpes simplex, Ebola, and HIV associated with different coagulopathy degrees and thrombosis [ 48 , 49 ]. However, there is a gap in the knowledge about the exact mechanism of TF induction and release upon viral infections [ 17 ].…”

“…It is known that COVID-19 induces an important coagulopathy in which multiple components are involved in immunothrombosis and play an essential role [ 50 , 51 ]. First, infected endothelial cells release VWF, attracting local neutrophils and platelets that promote inflammation and coagulation [ 17 ]. Moreover, COVID-19 provokes endothelial cell damage and apoptosis, leading to a decrease in antithrombotic activity [ 52 ].…”