Interleukin-22 (IL-22) signaling pathway (IL-22 pathway)

The Interleukin-22 (IL-22) signaling pathway is a critical axis in mucosal immunity and tissue homeostasis, primarily involving the cytokine IL-22 and its heterodimeric receptor complex composed of IL-22R1 and IL-10R2 (PMID: 24507152). Unlike many other cytokines, IL-22 acts almost exclusively on non-hematopoietic cells, such as epithelial cells in the skin, gut, and lungs, as well as hepatocytes, due to the restricted expression of the IL-22R1 subunit (UniProt: Q8N6P7). Upon binding, IL-22 triggers the JAK/STAT signaling cascade, predominantly activating STAT3 to promote cell survival, proliferation, and the production of antimicrobial peptides like S100 proteins and defensins (PMID: 29461516). In diseases like psoriasis and atopic dermatitis, overactivation of this pathway contributes to epithelial hyperplasia and chronic inflammation, making IL-22 inhibition with drugs like Fezakinumab a viable therapeutic strategy (PMID: 29461516). Conversely, in conditions like inflammatory bowel disease or acute liver injury, the pathway's regenerative properties are leveraged through IL-22 agonists or Fc-fusion proteins like F-652 to enhance tissue repair (ClinicalTrials.gov: NCT02406677). The dual nature of IL-22 as both a pro-inflammatory and tissue-protective mediator requires careful patient selection and monitoring due to potential pro-tumorigenic risks associated with chronic STAT3 activation (PMID: 23912183).

Other names

IL-22/IL-22R axisInterleukin-22 receptor complexIL-22 signaling

The pathway is targeted either through neutralization of the IL-22 ligand using monoclonal antibodies to treat inflammatory skin diseases or through the administration of recombinant IL-22-Fc fusion proteins to promote tissue regeneration and barrier repair in the gut and liver (PMID: 29461516, ClinicalTrials.gov: NCT02406677).