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bioRxiv · 10.1101/2025.02.11.637657

Neutrophil KLF2 regulates inflammasome-dependent neonatal mortality from endotoxemia

Mukherjee, D.·Satyavolu, S.·Thomas, A.·Cioffi, S.·Li, Y.·Chan, E. R.·Wen, K.·Huang, A.·Jain, M.·Dubyak, G.·Nayak, L.
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Abstract

Preterm neonates die at a significantly higher rate from sepsis than full-term neonates, attributable to their dysregulated immune response. 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, Kruppel-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 pro-inflammatory cytokine levels after endotoxemia compared to P4 controls or P12 pups, with significantly increased levels of IL-1{beta}, 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{beta} 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 pro-inflammatory pathways in a developmentally dependent manner. These data suggest that targeting KLF2 could be a novel strategy to decrease the pro-inflammatory cytokine storm in neonatal sepsis and improve survival in neonates with sepsis. Summary sentenceKLF2 regulates the developmental response to endotoxin in neonatal mice through the NLRP3 inflammasome signaling pathway.

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Mukherjee, D., Satyavolu, S., Thomas, A., Cioffi, S., Li, Y., Chan, E. R., Wen, K., Huang, A., Jain, M., Dubyak, G., Nayak, L.. 2025-02-15. Neutrophil KLF2 regulates inflammasome-dependent neonatal mortality from endotoxemia. https://doi.org/10.1101/2025.02.11.637657

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