The Toll-interleukin-1 receptor member SIGIRR regulates colonic epithelial homeostasis, inflammation, and tumorigenesis.
Despite constant contact with the large population of commensal bacteria, the colonic mucosa is normally hyporesponsive to these potentially proinflammatory signals. Here we report that the single immunoglobulin IL-1 receptor-related molecule (SIGIRR), a negative regulator for Toll-IL-1R signaling, plays a critical role in gut homeostasis, intestinal inflammation, and colitis-associated tumorigenesis by maintaining the microbial tolerance of the colonic epithelium. SIGIRR-deficient (Sigirr(-/-)) colonic epithelial cells displayed commensal bacteria-dependent homeostatic defects, as shown by constitutive upregulation of inflammatory genes, increased inflammatory responses to dextran sulfate sodium (DSS) challenge, and increased Azoxymethane (AOM)+DSS-induced colitis-associated tumorigenesis. Gut epithelium-specific expression of the SIGIRR transgene in the SIGIRR-deficient background reduced the cell survival of the SIGIRR-deficient colon epithelium, abrogated the hypersensitivity of the Sigirr(-/-) mice to DSS-induced colitis, and reduced AOM+DSS-induced tumorigenesis. Taken together, our results indicate that epithelium-derived SIGIRR is critical in controlling the homeostasis and innate immune responses of the colon to enteric microflora.
Xiao
Hui
H
Department of Immunology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Gulen
Muhammet Fatih
MF
Qin
Jinzhong
J
Yao
Jianhong
J
Bulek
Katarzyna
K
Kish
Danielle
D
Altuntas
Cengiz Zubeyir
CZ
Wald
David
D
Ma
Caixia
C
Zhou
Hang
H
Tuohy
Vincent K
VK
Fairchild
Robert L
RL
de la Motte
Carol
C
Cua
Daniel
D
Vallance
Bruce A
BA
Li
Xiaoxia
X
D000818:Animals; D001419:Bacteria / Q000276:immunology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology*; D018925:Chemokines / Q000235:genetics; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000276:immunology* / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics*; D007413:Intestinal Mucosa / Q000276:immunology / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism
D018925:Chemokines; D016328:NF-kappa B; D017472:Receptors, Interleukin-1; D050796:STAT3 Transcription Factor; C484529:SIGIRR protein, mouse