Mixed lineage kinase-like protein protects against Clostridium perfringens infection by enhancing NLRP3 inflammasome-extracellular traps axis

Despite intense research in understanding Clostridium perfringens (C. perfringens) pathogenesis, the mechanisms by which it is cleared from the host are largely unclarified. In C. perfringens gas gangrene and enterocolitis model, Mlkl−/− mice, lacking mixed lineage kinase-like protein (MLKL), are mo...

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Published iniScience Vol. 25; no. 10; p. 105121
Main Authors Liu, Yang, Xing, Li-Hua, Li, Fen-Xin, Wang, Na, Ma, Yu-Ze, Li, Jian-Wei, Wu, Yu-Jing, Liang, Jing, Lei, Yu-Xin, Wang, Xue-Yin, Meng, Fan-Hua, Yang, Yong-Jun, Li, Guang-Peng, Wang, Xiao, Yu, Shui-Xing
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 21.10.2022
Elsevier
Subjects
bacteriology
immune response
microbiology
Molecular biology
molecular microbiology
microbiology
bacteriology
molecular microbiology
Molecular biology
immune response
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Summary:Despite intense research in understanding Clostridium perfringens (C. perfringens) pathogenesis, the mechanisms by which it is cleared from the host are largely unclarified. In C. perfringens gas gangrene and enterocolitis model, Mlkl−/− mice, lacking mixed lineage kinase-like protein (MLKL), are more susceptible to C. perfringens infection. Mlkl deficiency results in a defect in inflammasome activation, and IL-18 and IL-1β releases. Exogenous administration of recombinant IL-18 is able to rescue the susceptibility of Mlkl−/− mice. Notably, K+ efflux-dependent NLRP3 inflammasome signaling downstream of active MLKL promotes bacterial killing and clearance. Interestingly, the defect of bactericidal activity is also mediated by decreased classical extracellular trap formation in the absence of Mlkl. Our results demonstrate that MLKL mediates extracellular trap formation in a NLRP3 inflammasome-dependent manner. These findings highlight the requirement of MLKL for host defense against C. perfringens infection through enhancing NLRP3 inflammasome-extracellular traps axis. [Display omitted] •MLKL is critical in limiting Clostridium perfringens gas gangrene and enterocolitis•MLKL deficiency leads to impaired potassium efflux-dependent NLRP3 signaling•MLKL mediates NLRP3 inflammasome signaling for extracellular traps formation•MLKL-NLRP3-extracellular traps axis facilitates pathogen control in vitro and in mice Molecular biology; Immune response; Microbiology; Bacteriology; Molecular microbiology
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ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2022.105121