IL-22 Signaling Dynamics in Intestinal Health and Inflammatory Bowel Disease

Interleukin-22 (IL-22) is a pivotal cytokine produced by Th17 cells and type 3 innate lymphoid cells that orchestrates epithelial homeostasis in the gut. Binding to its receptor IL-22RA1 on non-haematopoietic cells, IL-22 activates the STAT3 pathway to promote antimicrobial peptide secretion, mucin production and tissue repair. In steady state, this axis preserves barrier integrity and regulates cross-talk between the epithelium and commensal microbiota. In inflammatory bowel disease (IBD), dysregulated IL-22 signalling can contribute to both mucosal healing and pathological inflammation, depending on the local cytokine milieu and cellular context. Chronic overactivation raises the risk of colitis-associated neoplasia, whereas insufficient signalling impairs epithelial regeneration, highlighting the dualistic role of IL-22 in intestinal health and disease.

Research from Nature Portfolio

Recent studies have defined tissue-specific roles for IL-22RA1 signalling. In murine models of diet-induced obesity, intestinal epithelium-restricted IL-22RA1 drives transcriptional programmes that regulate lipid and glucose metabolism via microbiota-dependent mechanisms, with Paneth cell-specific signalling modulating systemic inflammation. Another investigation delineated an IL-22–STAT3–IL-18 circuit in colonic crypts: IL-22 engages STAT3 to induce IL-18, which in turn enhances Paneth cell antimicrobial function and Lgr5+ stem cell expansion, essential for barrier defence and clearance of adherent-invasive bacteria. These findings place IL-18 downstream of IL-22–STAT3 in orchestrating epithelial resilience against infection and inflammation.

IL-22 Signaling Dynamics in Intestinal Health and Inflammatory Bowel Disease publication trend

The graph below shows the total number of articles in il-22 signaling dynamics in intestinal health and inflammatory bowel disease across all publications each year (not limited to Nature Index journals).

Technical terms

IL-22: Cytokine from Th17 cells and ILC3 that acts on epithelial cells to regulate immunity and regeneration.

IL-22RA1: Receptor subunit on non-haematopoietic cells mediating IL-22 signal transduction.

STAT3: Transcription factor phosphorylated downstream of IL-22RA1, driving genes for barrier integrity.

MATH1: Transcription factor marking goblet and progenitor cells involved in mucin production.

Paneth cells: Secretory epithelial cells that produce antimicrobial peptides and support stem cell niches.

ILC3: Innate lymphoid cell subset that secretes IL-22 to maintain mucosal immunity.

O-glycosylation: Attachment of sugar moieties to mucin proteins, essential for mucus barrier function.

References

1. Intestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders. Nature Communications (2024).
2. IL-22 initiates an IL-18-dependent epithelial response circuit to enforce intestinal host defence. Nature Communications (2022).
3. IL-22 promotes mucin-type O-glycosylation and MATH1+ cell-mediated amelioration of intestinal inflammation. Cell Reports (2024).
4. Inulin diet uncovers complex diet-microbiota-immune cell interactions remodeling the gut epithelium. Microbiome (2023).
5. Bacteroides fragilis strain ZY-312 facilitates colonic mucosa regeneration in colitis via motivating STAT3 signaling pathway induced by IL-22 from ILC3 secretion. Frontiers in Immunology (2023).