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In addition to tissue destruction caused directly by bacterial invasion, an overwhelming cytokine response by the immune cells to bacterial antigens also results in collateral damage. Sepsis leads to decreased gene expression of a critical transcription factor, Kr\u00fcppel-like factor-2 (KLF2), a tonic repressor of myeloid cell activation. Using a murine model of myeloid-Klf2 deletion, we show that loss of KLF2 is associated with decreased survival after endotoxemia in a developmentally dependent manner, with increased mortality at postnatal day 4 (P4) compared to P12 pups. This survival is significantly increased by neutrophil depletion. P4 knockout pups have increased proinflammatory cytokine levels after endotoxemia compared to P4 controls or P12 pups, with significantly increased levels of IL-1\u03b2, a product of the activation of the NLRP3 inflammasome complex. Loss of myeloid-KLF2 at an earlier postnatal age leads to a greater increase in NLRP3 priming and activation and greater IL-1\u03b2 release by BMNs. Inhibition of NLRP3 inflammasome activation by MCC950 significantly increased survival after endotoxemia in P4 pups. Transcriptomic analysis of bone marrow neutrophils showed that loss of myeloid-KLF2 is associated with gene enrichment of proinflammatory pathways in a developmentally dependent manner. These data suggest that targeting KLF2 could be a novel strategy to decrease the proinflammatory cytokine storm in neonatal sepsis and improve survival in neonates with sepsis.<\/jats:p>","DOI":"10.1093\/jleuko\/qiaf040","type":"journal-article","created":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T02:45:51Z","timestamp":1743561951000},"source":"Crossref","is-referenced-by-count":3,"title":["Neutrophil KLF2 regulates inflammasome-dependent neonatal mortality from endotoxemia"],"prefix":"10.1093","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6812-8970","authenticated-orcid":false,"given":"Devashis","family":"Mukherjee","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Case Western Reserve University School of Medicine (CWRUSOM) , 10900 Euclid Ave, Cleveland, OH 44106 ,","place":["United States"]},{"name":"Division of Neonatology, UH Rainbow Babies and Children's Hospital , 11100 Euclid Ave, Cleveland, OH 44106 ,","place":["United 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