Inflammasome Activation Triggers Blood Clotting and Host Death through Pyroptosis

Abstract

Inflammasome activation and subsequent pyroptosis are critical defense mechanisms against microbes. However, overactivation of inflammasome leads to death of the host. Although recent studies have uncovered the mechanism of pyroptosis following inflammasome activation, how pyroptotic cell death drives pathogenesis, eventually leading to death of the host, is unknown. Here, we identified inflammasome activation as a trigger for blood clotting through pyroptosis. We have shown that canonical inflammasome activation by the conserved type III secretion system (T3SS) rod proteins from Gramnegative bacteria or noncanonical inflammasome activation by lipopolysaccharide (LPS) induced systemic blood clotting and massive thrombosis in tissues. Following inflammasome activation, pyroptotic macrophages released tissue factor (TF), an essential initiator of coagulation cascades. Genetic or pharmacological inhibition of TF abolishes inflammasome-mediated blood clotting and protects against death. Our data reveal that blood clotting is the major cause of host death following inflammasome activation and demonstrate that inflammasome bridges inflammation with thrombosis.

Innate immunity to adenovirus: lessons from mice

“…The authors suggested that higher virus doses are needed to trigger complement-dependent thrombocytopenia as compared to complement-dependent inflammatory cytokine activation, which occurs after intravenous injection of even relatively low virus doses [106]. It was recently discovered that upon executing necrotic type death, macrophages release tissue factor (TF), one of the principal factors activating blood coagulation cascade [110]. It was determined that platelet activation occurs rapidly after their incubation with HAdv-C5 and that platelets express HAdv-C5 attachment receptor, CAR, suggesting that direct HAdv-C5 binding to CAR on platelets may be responsible for virus-mediated platelet activation.…”

“…Upon analysis of plasma levels of sCD62P and D-dimer, it was found that 6 h after intravenous virus administration, their concentrations were significantly higher compared to mock-treated mice, with the highest concentrations of D-dimer observed after intravenous administration of HAdv-C5, HAdv-B11, HAdv-B35, and HAdv-F41 [109]. It was recently discovered that upon executing necrotic type death, macrophages release tissue factor (TF), one of the principal factors activating blood coagulation cascade [110]. Because large numbers of Kupffer cells die via a necrotic type death after interaction with HAdv, it is plausible that Kupffer cells release TF, which activates systemic intravascular coagulation.…”

Vying for the control of inflammasomes: The cytosolic frontier of enteric bacterial pathogen–host interactions

“…In addition to T3SS effectors, structural T3SS components also provoke inflammasome activation. The inner rod protein EscI of the LEE‐encoded T3SS, the inner rod protein EprJ and the needle protein EprI of the E. coli type III secretion system 2 (ETT2) activate murine NLRC4 inflammasomes in vitro when introduced directly into the macrophage cytosol (Miao, Mao, et al, ; Zhao et al, ; Yang et al, ; Wu et al, ); however, the ETT2 has accumulated considerable mutational attrition and is not believed to form a functional T3SS (Ren et al, ). Critically, the EPEC T3SS needle protein EscF is one of the needle proteins that are not detected in human THP‐1 macrophages (Yang et al, ).…”

“…Activator (Knodler et al, 2014;Vanaja et al, 2016;Goddard et al, 2019) CASP4 ! NLRP3 Stx (EHEC) (Lee et al, 2016;Platnich et al, 2018) Tir and LPS (T3SSdependent) (EPEC) (Goddard et al, 2019) NLRP3 Haemolysin EhxA (EHEC) (Zhang et al, 2012;Cheng et al, 2015) Nlrp3 RNA:DNA (EHEC) (Vanaja et al, 2014) Naip2-Nlrc4 EscI (T3SS rod; EPEC/ EHEC), EprJ (ETT2 rod; EHEC) Zhao et al, 2011;Wu et al, 2019) NAIP-NLRC4 OR Naip1-Nlrc4…”

“…EprI (ETT2 needle; EHEC) (Yang et al, 2013;Zhao et al, 2016;Wu et al, 2019) NLRP3 NleA/EspI (EPEC) Inhibitor (Yen et al, 2015) CASP4/Casp11 NleF (EPEC) (Blasche et al, 2013;Pallett et al, 2017;Pollock et al, 2017) Salmonella Typhimurium…”