TY - JOUR
T1 - Epithelial Nlrp10 inflammasome mediates protection against intestinal autoinflammation
AU - Zheng, Danping
AU - Mohapatra, Gayatree
AU - Kern, Lara
AU - He, Yiming
AU - Shmueli, Merav D
AU - Valdés-Mas, Rafael
AU - Kolodziejczyk, Aleksandra A
AU - Próchnicki, Tomasz
AU - Vasconcelos, Matilde B
AU - Schorr, Lena
AU - Hertel, Franziska
AU - Lee, Ye Seul
AU - Rufino, Miguel Camacho
AU - Ceddaha, Emmanuelle
AU - Shimshy, Sandy
AU - Hodgetts, Ryan James
AU - Dori-Bachash, Mally
AU - Kleimeyer, Christian
AU - Goldenberg, Kim
AU - Heinemann, Melina
AU - Stettner, Noa
AU - Harmelin, Alon
AU - Shapiro, Hagit
AU - Puschhof, Jens
AU - Chen, Minhu
AU - Flavell, Richard A
AU - Latz, Eicke
AU - Merbl, Yifat
AU - Abdeen, Suhaib K
AU - Elinav, Eran
N1 - © 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2023/4/1
Y1 - 2023/4/1
N2 - 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.
AB - 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.
KW - Mice
KW - Humans
KW - Animals
KW - Inflammasomes/metabolism
KW - Apoptosis Regulatory Proteins/genetics
KW - Carrier Proteins/genetics
KW - Apoptosis
KW - Caspase 1/metabolism
KW - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
KW - Interleukin-1beta/metabolism
KW - Adaptor Proteins, Signal Transducing/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85150346360&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/579f1832-a183-3d54-ace4-2e3461372e13/
U2 - 10.1038/s41590-023-01450-z
DO - 10.1038/s41590-023-01450-z
M3 - Letter
C2 - 36941399
SN - 1529-2916
VL - 24
SP - 585
EP - 594
JO - Nature Immunology
JF - Nature Immunology
IS - 4
ER -