Exaggerated IL-15 and Altered Expression of foxp3+ Cell-Derived Cytokines Contribute to Enhanced Colitis in Nlrp3-/- Mice.
The pathogenesis of Crohn's disease (CD) involves defects in the innate immune system, impairing responses to microbes. Studies have revealed that mutations NLRP3 are associated with CD. We reported previously that Nlrp3-/- mice were more susceptible to colitis and exhibited reduced colonic IL-10 expression. In the current study, we sought to determine how the loss of NLRP3 might be altering the function of regulatory T cells, a major source of IL-10. Colitis was induced in wild-type (WT) and Nlrp3-/- mice by treatment with dextran sulphate sodium (DSS). Lamina propria (LP) cells were assessed by flow cytometry and cytokine expression was assessed. DSS-treated Nlrp3-/- mice exhibited increased numbers of colonic foxp3+ T cells that expressed significantly lower levels of IL-10 but increased IL-17. This was associated with increased expression of colonic IL-15 and increased surface expression of IL-15 on LP dendritic cells. Neutralizing IL-15 in Nlrp3-/- mice attenuated the severity of colitis, decreased the number of colonic foxp3+ cells, and reduced the colonic expression of IL-12p40 and IL-17. These data suggest that the NLRP3 inflammasome can regulate intestinal inflammation through noncanonical mechanisms, providing additional insight as to how NLRP3 variants may contribute to the pathogenesis of CD.
Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada T2N 4N1; Department of Microbiology, Immunology & Infectious Diseases, University of Calgary, Calgary, AB, Canada T2N 4N1.
Simon A
0000-0001-5782-1481
SA
Hirota
Department of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1.
Aito
0000-0002-9967-7200
A
Ueno
Department of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1.
Sarah E
SE
Tulk
Department of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1.
Helen M
HM
Becker
Department of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1; Department of Biochemistry & Molecular Biology, University of Calgary, Calgary, AB, Canada T2N 4N1.
L Patrick
0000-0001-5063-0447
LP
Schenck
Department of Biochemistry & Molecular Biology, University of Calgary, Calgary, AB, Canada T2N 4N1.
Mireille S
MS
Potentier
Department of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1.
Yan
Y
Li
Department of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1.
Subrata
S
Ghosh
Department of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1.
Daniel A
0000-0003-1757-218X
DA
Muruve
Department of Biochemistry & Molecular Biology, University of Calgary, Calgary, AB, Canada T2N 4N1.
Justin A
JA
MacDonald
Department of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1.
Paul L
PL
Beck
D000818:Animals; D003092:Colitis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism*; D003713:Dendritic Cells / Q000378:metabolism; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D058847:Inflammasomes / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D019409:Interleukin-15 / Q000378:metabolism*; D020381:Interleukin-17 / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000172:deficiency* / Q000235:genetics; D009195:Peroxidase / Q000378:metabolism
D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D058847:Inflammasomes; D019409:Interleukin-15; D020381:Interleukin-17; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D016753:Interleukin-10; D009195:Peroxidase