Interleukin-22 functions to alleviate hypoxia-induced intestinal inflammation by modulating pro- and...

Intestinal inflammation is a common challenge in intensive aquaculture, yet its pathogenesis remains unclear. While interleukin 22 (IL-22) is recognized as a critical regulator of cellular homeostasis during inflammation in higher vertebrates, its roles in fish are not well understood. This study established hypoxia-induced models in intestinal tissues and primary intestinal epithelial cells of yellow catfish to investigate the involvement of IL-22 in maintaining intestinal homeostasis. Results revealed that Pelteobagrus fulvidraco IL-22 ( Pf_ IL-22) was abundantly expressed in mucosal tissues, with the highest levels in the gill and intestine. Hypoxia induced pronounced intestinal injury, characterized by loosening of the lamina propria and extensive vacuolization, while activating hypoxia-inducible factor (HIF) signaling and markedly up-regulating IL-22 expression. IL-22 levels peaked at 24 h post-hypoxia, suggesting a role in early immune responses. Recombinant Pf_IL-22 also induced transcription of pro-inflammatory mediators, including IL-1β and tumor necrosis factor α (TNF-α), in primary intestinal epithelial cells, indicating a dual regulatory function in balancing protection and inflammation. Mechanistic analyses revealed that HIF-1α directly interacted with a hypoxia response element within the IL-22 promoter to drive transcription, as confirmed by dual-luciferase assays, electrophoretic mobility-shift assays, and HIF-1α knockdown. Silencing Pf_IL-22 significantly suppressed Th17 cell differentiation pathways, demonstrating its role in shaping downstream immune responses. These findings establish the HIF-1α/IL-22 axis as a key regulatory pathway modulating immune responses and alleviating intestinal inflammation, providing a basis for developing IL-22-targeted immunotherapies and selective breeding strategies in aquaculture.