Interleukin-22 functions to alleviate hypoxia-induced intestinal inflammation by modulating pro- and anti-inflammatory factors in Pelteobagrus filvidraco

Intestinal inflammation is a common issue in intensive aquaculture, yet its pathogenesis remains unclear. Interleukin 22 (IL-22) plays a key role in maintaining cellular homeostasis during inflammation in higher vertebrates, but studies in fish are limited. In this study, we established hypoxia models both in intestinal tissues and primary intestinal epithelial cells of yellow catfish to investigate the roles of IL-22 in intestinal homeostasis. The results revealed that <i>Pelteobagrus fulvidraco</i> IL-22 (<i>Pf_IL-22</i>) was highly expressed in mucosal tissues, particularly in the gill and intestine. Hypoxia induced intestinal structural damage, characterized by loosening of the lamina propria and increased vacuolization, while simultaneously activating the HIF signaling pathway and promoting IL-22 expression. IL-22 peaked at 24 h post hypoxia, indicating its involvement in anti-inflammatory immune responses. However, recombinant Pf_IL-22 can also activated inflammatory factors, including IL-1β and TNF-α, in primary intestinal epithelial cells, indicating its dual function in regulation. To further explore the underlying mechanisms, we investigated the HIF-1α/IL-22 inflammasome axis and its downstream immune signaling responses. Dual-luciferase reporter assays revealed that HIF-1α can binds to the IL-22 promoter's hypoxia response element to activate IL-22 expression. Electrophoretic mobility-shift and HIF-1α interference assays confirmed this interaction. Moreover, knockdown of <i>Pf_IL-22</i> significantly inhibited Th17 cell differentiation signaling pathway, highlighting the way of IL-22 involved in regulating intestinal inflammation. In conclusion, our findings underscore the importance of HIF-1α/IL-22 axis in modulating immune responses and alleviating intestinal inflammation, offering insights for IL-22-based immune agents and aquaculture breeding strategies.