Evolutionarily conserved IL-22 participates in gut mucosal barrier through its receptors IL-22BP, IL-10R2 and IL-22RA1 during bacterial infection in teleost

IL-22 is a critical cytokine of epithelial mucosal barrier. In humans, IL-22 signals through a heteroduplex receptor consisting of IL-22R and IL-10R beta. In fish, IL-22 and its receptors homologues have been cloned in a number of species, however, no studies have been reported how the receptors are involved in IL-22 transduction. For this purpose, in this study we identified IL-22 and its soluble receptor IL-22BP and transmembrane receptors IL-22RA1 and IL-10R2 in Carassius cuvieri x Carassius auratus red var. (named WR-IL-22, WR-IL-22BP, WR-IL10R2 and WR-IL22RA1, respectively). WR-IL-22, WR-IL-22BP, WR-IL10R2 and WR-IL22RA1 were relatively conserved in the evolutionary process, sharing the same conserved domains as their higher vertebrate homo-logues. When the fish were infected with the Aeromonas hydrophila, the expression of WR-IL-22, WR-IL-22BP, WR-IL10R2 and WR-IL22RA1 were significantly induced in the gut. The co-IP assay showed that WR-IL-22 not only interacted with WR-IL-22BP, but also with WR-IL10R2 and WR-IL22RA1. When introduced in vivo, WR-IL-22 activated the JAK1-STAT3 axis and protected the gut mucosa from A. hydrophila infection. However, over -expression of WR-IL-22BP or knockdown of transmembrane receptors WR-IL10R2 and WR-IL22RA1 significantly inhibited the activation of WR-IL-22-mediated JAK1-STAT3 axis and promoted bacterial colonization in the gut. These results provided new insights into the role of IL-22 and its receptors in the gut mucosa barrier and immune response in teleost.