Inflammasome Activation-Induced Hypercoagulopathy: Impact on Cardiovascular Dysfunction Triggered in COVID-19 Patients

Abstract

Coronavirus disease 2019 (COVID-19) is the most devastating infectious disease in the 21st century with more than 2 million lives lost in less than a year. The activation of inflammasome in the host infected by SARS-CoV-2 is highly related to cytokine storm and hypercoagulopathy, which significantly contribute to the poor prognosis of COVID-19 patients. Even though many studies have shown the host defense mechanism induced by inflammasome against various viral infections, mechanistic interactions leading to downstream cellular responses and pathogenesis in COVID-19 remain unclear. The SARS-CoV-2 infection has been associated with numerous cardiovascular disorders including acute myocardial injury, myocarditis, arrhythmias, and venous thromboembolism. The inflammatory response triggered by the activation of NLRP3 inflammasome under certain cardiovascular conditions resulted in hyperinflammation or the modulation of angiotensin-converting enzyme 2 signaling pathways. Perturbations of several target cells and tissues have been described in inflammasome activation, including pneumocytes, macrophages, endothelial cells, and dendritic cells. The interplay between inflammasome activation and hypercoagulopathy in COVID-19 patients is an emerging area to be further addressed. Targeted therapeutics to suppress inflammasome activation may have a positive effect on the reduction of hyperinflammation-induced hypercoagulopathy and cardiovascular disorders occurring as COVID-19 complications.

Keywords: COVID-19; NLRP3; cardiovascular complications; hypercoagulopathy; inflammation.

Figure 1

Mechanisms of inflammasome activation and clot formation. (A,B) TLR detects the presence of microbes (LPS) and activates the NF-kB that initiates the priming phase by transcribing the pro-IL-1β. Then, coupled with endogenous signals, the inflammasome components will be assembled and activate the procaspase-1. (C) Blood vessel damage, activated platelets, and hypoxia-inducible factors have been shown in thrombosis activation. Macrophages and neutrophils migrate and release their danger signals to the damaged vessels, including ROS, ATP, and dsDNA, contributing to the development of inflammasome complexes. Activated caspase-1 in turn activates pro-IL-1β and IL-18. Active caspase-1 further activates the GSDMD transmembrane protein associated with membrane pore formation, destabilization, and cell membrane rupture (pyroptosis). Inflammation and pyroptosis are enhanced by activated caspase-1, leading to thrombosis. AIM2, after sensing the dsDNA released from the pyroptotic cells, will form inflammatory complexes and cleave the procaspase-1 to become the active caspase-1. MPs derived from activated cells contain TFs, which initiate the coagulation system and cause blood clot formation. (D) Activated proinflammatory cytokines increase inflammation and cause cytokine storms and induce blood clotting. AIM2, absent in melanoma 2; ATP, adenosine triphosphate; Ca, calcium; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; DAMPs, damage-associated molecular patterns; dsDNA, double stranded deoxyribonucleic acid; GSDMD, Gasdermin D; HIF-1α, hypoxia inducible factor one alpha; IL-1β, Interleukin 1 beta; IL-18, Interleukin18; LPS, lipopolysaccharide; MPs, microparticles; NET, neutrophil extracellular trap; NF-kB, nuclear factor kappa light chain stimulation of activated B cells; NLRP3, nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3 protein; PAMPs, pathogen-associated molecular patterns; ROS, reactive oxygen specious; TFs, tissue factors; TLR, toll-like receptor.

Figure 2

Therapeutic targets in inflammasome induced cardiovascular disorders in COVID-19. SARS-CoV-2, the causative agent for COVID-19, causes pulmonary infection. Inflammasomes are activated in SARS-CoV-2 infected patients. Activation of NLRP3 inflammasome results in hyperinflammation and hypercoagulopathy, which ultimately leads to cardiovascular complications in COVID-19. Various therapeutic compounds are indicated in inhibiting the pathways leading to the inflammasome activation and preventing cardiovascular risks. ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; Ca, calcium; CaSR, calcium-sensing receptor, CCE, cholecalciferol cholesterol emulsion; CD, cluster of differentiation; DAMPs, damage-associated molecular patterns; GSDMD, gasdermin D; HIF-1α, hypoxia inducible factor one alpha; IL-1β, Interleukin 1 beta; IL-18, Interleukin 18; IRAK, interleukin-1 receptor-associated kinase; LDL, low density lipoprotein; LPS, lipopolysaccharide; MPs, micro-particles; NLRP3, nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3 protein; PAMPs, pathogen-associated molecular patterns; SARS-CoV-2, severe acute respiratory syndrome coronavirus two; TFs, tissue factors; TLR 4, toll-like receptor.