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

Area of Science:

• Immunology
• Gastroenterology
• Genetics

Background:

• Interleukin 10 receptor (IL10R) signaling is crucial for immune homeostasis.
• Loss-of-function mutations in IL10R cause severe infant-onset inflammatory bowel disease (IBD).
• IL10R deficiency in macrophages is linked to increased interleukin 1β (IL1β) production.

Purpose of the Study:

• To investigate the role of IL1β in colitis development in IL10R-deficient mice.
• To explore the mechanisms of IL1β dysregulation in IL10R deficiency.
• To evaluate the therapeutic potential of IL1 receptor blockade in IL10R-deficient IBD patients.

Main Methods:

• Utilized IL10R-deficient mouse models of colitis.
• Analyzed macrophage inflammasome activation and cytokine production.
• Assessed the impact of T cell-specific IL1 receptor expression on colitis severity.
• Treated IL10R-deficient patients with anakinra, an IL1 receptor antagonist.

Main Results:

• Innate immune production of IL1β mediates colitis in IL10R-deficient mice.
• IL10R deficiency leads to enhanced inflammasome activation and IL1β secretion in macrophages.
• IL1 receptor blockade with anakinra resulted in significant clinical, endoscopic, and histologic improvements in IBD patients.
• Anakinra treatment served as a bridge to transplantation in one patient.

Conclusions:

• Loss of IL10R signaling promotes intestinal inflammation partly through increased IL1β production by innate immune cells.
• IL1β activation of CD4+ T cells contributes to the pathogenesis of IL10R-deficient IBD.
• Targeting IL1 signaling represents a promising therapeutic strategy for IBD associated with IL10R deficiency.