The tissue protective functions of interleukin-22 can be decoupled from pro-inflammatory actions through structure-based design.

ABSTRACT: Interleukin-22 (IL-22) acts on epithelial cells to promote tissue protection and regeneration, but can also elicit pro-inflammatory effects, contributing to disease pathology. Here, we engineered a high-affinity IL-22 super-agonist that enabled the structure determination of the IL-22-IL-22Rα-IL-10Rβ ternary complex to a resolution of 2.6 Å. Using structure-based design, we systematically destabilized the IL-22-IL-10Rβ binding interface to create partial agonist analogs that decoupled downstream STAT1 and STAT3 signaling. The extent of STAT bias elicited by a single ligand varied across tissues, ranging from full STAT3-biased agonism to STAT1/3 antagonism, correlating with IL-10Rβ expression levels. In vivo, this tissue-selective signaling drove tissue protection in the pancreas and gastro

SUBMITTER: Saxton RA 

PROVIDER: S-EPMC8054646 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature