Interleukin 1β Mediates Intestinal Inflammation in Mice and Patients With Interleukin 10 Receptor Deficiency

doi:10.1053/j.gastro.2016.08.055

Gastroenterology

Volume 151, Issue 6, December 2016, Pages 1100-1104

https://doi.org/10.1053/j.gastro.2016.08.055 Get rights and content

Interleukin 10 receptor (IL10R)−deficient mice develop spontaneous colitis and, similarly, patients with loss-of-function mutations in IL10R develop severe infant-onset inflammatory bowel disease. Loss of IL10R signaling in mouse and human macrophages is associated with increased production of interleukin 1β. We demonstrated that innate immune production of IL1β mediates colitis in IL10R-deficient mice. Transfer of Il1r1^−/− CD4⁺ T cells into Rag1^−/−/Il10rb^−/− mice reduced the severity of their colitis (compared to mice that received CD4⁺ T cells that express IL1R), accompanied by decreased production of interferon gamma, tumor necrosis factor−α, and IL17A. In macrophages from mice without disruption of IL10R signaling or from healthy humans (controls), incubation with IL10 reduced canonical activation of the inflammasome and production of IL1β through transcriptional and post-translational regulation of NLRP3. Lipopolysaccharide and adenosine triphosphate stimulation of macrophages from Il10rb^−/− mice or IL10R-deficient patients resulted in increased production of IL1β. Moreover, in human IL10R-deficient macrophages, lipopolysaccharide stimulation alone triggered IL1β secretion via non-canonical, caspase 8−dependent activation of the inflammasome. We treated 2 IL10R-deficient patients with severe and treatment-refractory infant-onset inflammatory bowel disease with the IL1−receptor antagonist anakinra. Both patients had marked clinical, endoscopic, and histologic responses after 4–7 weeks. This treatment served as successful bridge to allogeneic hematopoietic stem cell transplantation in 1 patient. Our findings indicate that loss of IL10 signaling leads to intestinal inflammation, at least in part, through increased production of IL1 by innate immune cells, leading to activation of CD4⁺ T cells. Agents that block IL1 signaling might be used to treat patients with inflammatory bowel disease resulting from IL10R deficiency.

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Acknowledgments

Very Early Onset Inflammatory Bowel Disease International Consortium: Dror S. Shouval, Amlan Biswas, Alexandra E. Griffith, Liza Konnikova, Michael Field, Anthony Loizides, Batia Weiss, Baruch Yerushalmi, Tadahiro Yanagi, Aleixo M. Muise, Christoph Klein, Bruce H. Horwitz, Sarah C. Glover, and Athos Bousvaros.

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: Conflicts of interest The authors disclose no conflicts.

: Funding Dror S. Shouval is a recipient of a Research Fellowship Award Grant from the Crohn’s and Colitis Foundation of America (CCFA). Amlan Biswas is recipient of CCFA Career Development Award and National Institutes of Health (NIH) KO1 award (K01DK109026). Yu Hui Kang is a recipient of an A*STAR National Science Scholarship (Singapore). Scott B. Snapper is supported by NIH Grant DK034854, the Helmsley Charitable Trust, the Translational Investigator Service at Boston Children's Hospital, and the Wolpow Family Chair in IBD Treatment and Research.

: Author names in bold designate shared co-first authorship.

^∗: Authors share co-first authorship.

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Original ResearchBrief ReportInterleukin 1β Mediates Intestinal Inflammation in Mice and Patients With Interleukin 10 Receptor Deficiency

Section snippets

Acknowledgments

Adv Immunol

Gastroenterology

Immunity

Immunity

Mucosal Immunol

Immunity

Cell

Immunity

Original Research
Brief Report
Interleukin 1β Mediates Intestinal Inflammation in Mice and Patients With Interleukin 10 Receptor Deficiency