Epithelial Nlrp10 inflammasome mediates protection against intestinal autoinflammation.

Unlike other nucleotide oligomerization domain-like receptors, Nlrp10 lacks a canonical leucine-rich repeat domain, suggesting that it is incapable of signal sensing and inflammasome formation. Here we show that mouse Nlrp10 is expressed in distal colonic intestinal epithelial cells (IECs) and modulated by the intestinal microbiome. In vitro, Nlrp10 forms an Apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC)-dependent, m-3M3FBS-activated, polyinosinic:polycytidylic acid-modulated inflammasome driving interleukin-1β and interleukin-18 secretion. In vivo, Nlrp10 signaling is dispensable during steady state but becomes functional during autoinflammation in antagonizing mucosal damage. Importantly, whole-body or conditional IEC Nlrp10 depletion leads to reduced IEC caspase-1 activation, coupled with enhanced susceptibility to dextran sodium sulfate-induced colitis, mediated by altered inflammatory and healing programs. Collectively, understanding Nlrp10 inflammasome-dependent and independent activity, regulation and possible human relevance might facilitate the development of new innate immune anti-inflammatory interventions. © 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.

Citation

Danping Zheng, Gayatree Mohapatra, Lara Kern, Yiming He, Merav D Shmueli, Rafael Valdés-Mas, Aleksandra A Kolodziejczyk, Tomasz Próchnicki, Matilde B Vasconcelos, Lena Schorr, Franziska Hertel, Ye Seul Lee, Miguel Camacho Rufino, Emmanuelle Ceddaha, Sandy Shimshy, Ryan James Hodgetts, Mally Dori-Bachash, Christian Kleimeyer, Kim Goldenberg, Melina Heinemann, Noa Stettner, Alon Harmelin, Hagit Shapiro, Jens Puschhof, Minhu Chen, Richard A Flavell, Eicke Latz, Yifat Merbl, Suhaib K Abdeen, Eran Elinav. Epithelial Nlrp10 inflammasome mediates protection against intestinal autoinflammation. Nature immunology. 2023 Apr;24(4):585-594

Mesh Tags

Substances

PMID: 36941399

search → result