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

Dror S. Shouval, Amlan Biswas, Yu Hui Kang, Alexandra E. Griffith, Liza Konnikova, Ivan D. Mascanfroni, Naresh S. Redhu, Sandra M. Frei, Michael Field, Andria L. Doty, Jeffrey D. Goldsmith, Atul K. Bhan, Anthony Meneloas Loizides, Batia Weiss, Baruch Yerushalmi, Tadahiro Yanagi, Xiuli Lui, Francisco J. Quintana, Aleixo M. Muise, Christoph Klein & 4 others Bruce H. Horwitz, Sarah C. Glover, Athos Bousvaros, Scott B. Snapper

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1100-1104
Number of pages5
JournalGastroenterology
Volume151
Issue number6
DOIs
StatePublished - Dec 1 2016

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Interleukin-10 Receptors
Interleukin-1
Inflammation
Colitis
Inflammatory Bowel Diseases
Inflammasomes
Macrophages
T-Lymphocytes
Interleukin-10
Lipopolysaccharides
Interleukin 1 Receptor Antagonist Protein
Hematopoietic Stem Cell Transplantation
Caspases
Interferon-gamma
Tumor Necrosis Factor-alpha
Adenosine Triphosphate

Keywords

  • Caspase-1
  • Treg Cell
  • Ubiquitination
  • VEOIBD

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Shouval, D. S., Biswas, A., Kang, Y. H., Griffith, A. E., Konnikova, L., Mascanfroni, I. D., ... Snapper, S. B. (2016). Interleukin 1β Mediates Intestinal Inflammation in Mice and Patients With Interleukin 10 Receptor Deficiency. Gastroenterology, 151(6), 1100-1104. https://doi.org/10.1053/j.gastro.2016.08.055

Interleukin 1β Mediates Intestinal Inflammation in Mice and Patients With Interleukin 10 Receptor Deficiency. / Shouval, Dror S.; Biswas, Amlan; Kang, Yu Hui; Griffith, Alexandra E.; Konnikova, Liza; Mascanfroni, Ivan D.; Redhu, Naresh S.; Frei, Sandra M.; Field, Michael; Doty, Andria L.; Goldsmith, Jeffrey D.; Bhan, Atul K.; Loizides, Anthony Meneloas; Weiss, Batia; Yerushalmi, Baruch; Yanagi, Tadahiro; Lui, Xiuli; Quintana, Francisco J.; Muise, Aleixo M.; Klein, Christoph; Horwitz, Bruce H.; Glover, Sarah C.; Bousvaros, Athos; Snapper, Scott B.

In: Gastroenterology, Vol. 151, No. 6, 01.12.2016, p. 1100-1104.

Research output: Contribution to journalArticle

Shouval, DS, Biswas, A, Kang, YH, Griffith, AE, Konnikova, L, Mascanfroni, ID, Redhu, NS, Frei, SM, Field, M, Doty, AL, Goldsmith, JD, Bhan, AK, Loizides, AM, Weiss, B, Yerushalmi, B, Yanagi, T, Lui, X, Quintana, FJ, Muise, AM, Klein, C, Horwitz, BH, Glover, SC, Bousvaros, A & Snapper, SB 2016, 'Interleukin 1β Mediates Intestinal Inflammation in Mice and Patients With Interleukin 10 Receptor Deficiency', Gastroenterology, vol. 151, no. 6, pp. 1100-1104. https://doi.org/10.1053/j.gastro.2016.08.055
Shouval, Dror S. ; Biswas, Amlan ; Kang, Yu Hui ; Griffith, Alexandra E. ; Konnikova, Liza ; Mascanfroni, Ivan D. ; Redhu, Naresh S. ; Frei, Sandra M. ; Field, Michael ; Doty, Andria L. ; Goldsmith, Jeffrey D. ; Bhan, Atul K. ; Loizides, Anthony Meneloas ; Weiss, Batia ; Yerushalmi, Baruch ; Yanagi, Tadahiro ; Lui, Xiuli ; Quintana, Francisco J. ; Muise, Aleixo M. ; Klein, Christoph ; Horwitz, Bruce H. ; Glover, Sarah C. ; Bousvaros, Athos ; Snapper, Scott B. / Interleukin 1β Mediates Intestinal Inflammation in Mice and Patients With Interleukin 10 Receptor Deficiency. In: Gastroenterology. 2016 ; Vol. 151, No. 6. pp. 1100-1104.
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AU - Shouval, Dror S.

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