The NLRP1 inflammasome attenuates colitis and colitis-associated tumorigenesis.
Nucleotide-binding domain and leucine-rich repeat (NLR) proteins are a diverse family of pattern recognition receptors that are essential mediators of inflammation and host defense in the gastrointestinal system. Recent studies have identified a subgroup of inflammasome forming NLRs that modulate the mucosal immune response during inflammatory bowel disease (IBD) and colitis associated tumorigenesis. To better elucidate the contribution of NLR family members in IBD and cancer, we conducted a retrospective analysis of gene expression metadata from human patients. These data revealed that NLRP1, an inflammasome forming NLR, was significantly dysregulated in IBD and colon cancer. To better characterize the function of NLRP1 in disease pathogenesis, we used Nlrp1b(-/-) mice in colitis and colitis-associated cancer models. In this paper, we report that NLRP1 attenuates gastrointestinal inflammation and tumorigenesis. Nlrp1b(-/-) mice demonstrated significant increases in morbidity, inflammation, and tumorigenesis compared with wild-type animals. Similar to data previously reported for related inflammasome forming NLRs, the increased inflammation and tumor burden was correlated with attenuated levels of IL-1β and IL-18. Further mechanistic studies using bone marrow reconstitution experiments revealed that the increased disease pathogenesis in the Nlrp1b(-/-) mice was associated with nonhematopoietic-derived cells and suggests that NLRP1 functions in the colon epithelial cell compartment to attenuate tumorigenesis. Taken together, these data identify NLRP1 as an essential mediator of the host immune response during IBD and cancer. These findings are consistent with a model whereby multiple NLR inflammasomes attenuate disease pathobiology through modulating IL-1β and IL-18 levels in the colon.
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061.
Tere M
TM
Williams
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061.
Rachel A
RA
Leeth
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061.
Daniel E
DE
Rothschild
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061.
Sheryl L
SL
Coutermarsh-Ott
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061.
Dylan K
DK
McDaniel
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061.
Alysha E
AE
Simmons
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061.
Bettina
B
Heid
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061.
Thomas E
TE
Cecere
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061 icallen@vt.edu.
Irving C
IC
Allen
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001706:Biopsy; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D003092:Colitis / Q000139:chemically induced / Q000150:complications* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003093:Colitis, Ulcerative / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000070576:NLR Proteins; D012189:Retrospective Studies
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000070576:NLR Proteins; C427903:NLRP1 protein, human