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- W4319432079 abstract "Abstract Despite prompt intervention with antibiotics and surgical debridement, morbidity and mortality due to Group A Streptococcal Necrotizing Fasciitis (GAS-NF), frequently associated with streptococcal toxic shock, remain as high as 50%. The pathways driving the sequelae of effector responses that include an uncoordinated activation of the host immune system and inflammatory cytokine storm are not completely elucidated. Our previous studies demonstrated a central role for the pro-inflammatory mediator, IL-1b, in modulating the severity and survival in a mouse model of GAS-NF. To fine-tune IL-1b levels while simultaneously attenuating GAS multiplication and toxin synthesis, here, we investigated the effect of MCC950 (MCC), a small molecule inhibitor for NLRP3 inflammasome activation as a host-directed adjunct to clindamycin (CLN) (10mg/kg each, everyday X 5 days) in a mouse model of GAS NF. Survival outcomes did not differ between CLN and CLNMCC groups. Yet, CLNMCC significantly reduced skin mRNA levels of IL-1a, IL-1b, IL-33, and TNF-a, protein levels of the active fragment of caspase-1 and increased the ratio of pro: active caspase-1 (but not ASC or NLRP3) that coincided with reduced levels of circulating neutrophils. CLNMCC treatment significantly reduced tissue damage, levels of plasma IL-10, IL-1β, and circulating CD11b+LY6G+ granulocytic myeloid subsets. These results indicate that NLRP3 inflammasome activation may be primarily involved in excess IL-1b release, neutrophil influx, and tissue damage during GAS-NF. The evidence of improved outcomes suggests, in part, a beneficial efficacy of MCC950 to target NLRP3 as a feasible adjunct to CLN and mitigate inflammation and pathology with no adverse effects or delayed toxicity" @default.
- W4319432079 created "2023-02-09" @default.
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- W4319432079 date "2021-05-01" @default.
- W4319432079 modified "2023-09-27" @default.
- W4319432079 title "NLRP3 inflammasome inhibitor as an adjunct host-directed therapy in a hyper susceptible mouse model of Group A Streptococcal Necrotizing Fasciitis." @default.
- W4319432079 doi "https://doi.org/10.4049/jimmunol.206.supp.110.17" @default.
- W4319432079 hasPublicationYear "2021" @default.
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