IL-23-producing IL-10Rα-deficient gut macrophages elicit an IL-22-driven proinflammatory epithelial cell response

Area of Science:

• Immunology
• Gastroenterology
• Cell Biology

Background:

• Cytokines are crucial for intestinal health, but intercellular communication networks are not fully understood.
• Macrophages act as immune sentinels in the gut, maintaining homeostasis.
• Defects in interleukin-10 receptor (IL-10R) signaling are linked to inflammatory bowel diseases (IBD).

Purpose of the Study:

• To investigate the role of macrophage-specific IL-10 receptor deficiency in inducing intestinal inflammation.
• To identify the key molecular mediators driving colitis in this model.
• To elucidate the epithelial response to inflammatory macrophages in the context of IBD.

Main Methods:

• Generation of a murine model with macrophage-restricted IL-10 receptor deficiency (Cx3cr1Cre:Il10rafl/fl mice).
• Analysis of colitis development and severity in wild-type and knockout mice.
• Assessment of cytokine production (IL-23, IL-22) by macrophages and T cells.
• Evaluation of epithelial chemokine expression and neutrophil recruitment.

Main Results:

• Macrophage-restricted IL-10 receptor deficiency leads to spontaneous, severe colitis.
• Macrophage-derived IL-23 is identified as the primary driver of this pathology.
• Mice deficient for both IL-10R and IL-23 in macrophages (Cx3cr1Cre:Il10rafl/fl:Il23afl/fl) are protected from colitis.
• T cells in colitic mice produce IL-22, promoting epithelial chemokine expression and neutrophil influx.

Conclusions:

• Macrophage-specific IL-10R signaling is critical for preventing intestinal inflammation.
• Macrophage-derived IL-23 is a key pathogenic factor in this IBD model.
• This study defines macrophage-centric mechanisms contributing to colitis induction and pathogenesis, relevant to human IBD.