Interleukin 1β Mediates Intestinal Inflammation in Mice and Patients With Interleukin 10 Receptor Deficiency.
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.
Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.|Division of Pediatric Gastroenterology and Nutrition, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA.
Dror S
DS
Shouval
Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.|VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA.
Amlan
A
Biswas
Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
Yu Hui
YH
Kang
Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.|VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA.
Alexandra E
AE
Griffith
Harvard Medical School, Boston, MA, USA.|Divsion of Newborn Medicine, Brigham and Women's Hospital, Boston, MA, USA.|VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA.
Liza
L
Konnikova
Harvard Medical School, Boston, MA, USA.|Ann Romney Center for Neurological Diseases, Brigham and Women's Hospital, Boston, MA, USA.
Ivan D
ID
Mascanfroni
Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
Naresh S
NS
Redhu
Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
Sandra M
SM
Frei
Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.|VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA.
Michael
M
Field
Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Immunology and Laboratory Medicine and, University of Florida, FL, USA.
Andria L
AL
Doty
Harvard Medical School, Boston, MA, USA.|Department of Pathology, Boston Children's Hospital, Boston, MA, USA.
Jeffrey D
JD
Goldsmith
Harvard Medical School, Boston, MA, USA.|Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
Atul K
AK
Bhan
Division of Gastroenterology and Nutrition, The Children's Hospital at Montefiore, Bronx, NY, USA.|VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA.
Anthony
A
Loizides
Division of Pediatric Gastroenterology and Nutrition, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA.
Batia
B
Weiss
Pediatric Gastroenterology Unit, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.|VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA.
Baruch
B
Yerushalmi
Department of Pediatrics, Kurume University School of Medicine, Kurume, Japan.|VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA.
Tadahiro
T
Yanagi
Department of Pathology, Immunology and Laboratory Medicine and, University of Florida, FL, USA.
Xiuli
X
Lui
Harvard Medical School, Boston, MA, USA.|Ann Romney Center for Neurological Diseases, Brigham and Women's Hospital, Boston, MA, USA.
Francisco J
FJ
Quintana
Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada.|Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, ON, Canada.|Institute of Medical Science, and Department of Biochemistry, University of Toronto, Toronto, ON, Canada.|VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA.
Aleixo M
AM
Muise
Dr von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.|VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA.
Christoph
C
Klein
Harvard Medical School, Boston, MA, USA.|Department of Pathology Brigham and Women's Hospital, Boston, MA, USA.|VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA.
Bruce H
BH
Horwitz
Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Immunology and Laboratory Medicine and, University of Florida, FL, USA.|VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA.
Sarah C
SC
Glover
Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.|VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA.
Athos
A
Bousvaros
Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.|VEO-IBD International Consortium, Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA.
Scott B
SB
Snapper
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000328:Adult; D000818:Animals; D018501:Antirheumatic Agents / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes; D053181:Caspase 8 / Q000378:metabolism; D002478:Cells, Cultured; D002675:Child, Preschool; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use; D016753:Interleukin-10 / Q000378:metabolism* / Q000494:pharmacology; D053709:Interleukin-10 Receptor alpha Subunit / Q000235:genetics; D020381:Interleukin-17 / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D053701:Receptors, Interleukin-10 / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018501:Antirheumatic Agents; D018398:Homeodomain Proteins; D058847:Inflammasomes; D053590:Interleukin 1 Receptor Antagonist Protein; D053709:Interleukin-10 Receptor alpha Subunit; D020381:Interleukin-17; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D053701:Receptors, Interleukin-10; D014409:Tumor Necrosis Factor-alpha; C064658:RAG-1 protein; D016753:Interleukin-10; D007371:Interferon-gamma; D000255:Adenosine Triphosphate; D053181:Caspase 8
Caspase-1; Treg Cell; Ubiquitination; VEOIBD
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