Interleukin-22 receptor 1 upregulation and activation in hypoxic endothelial cells improves perfusion recovery in experimental peripheral arterial disease.

Inflammation induced by muscle ischemia is involved in tissue repair and perfusion recovery in peripheral arterial disease (PAD) patients. Interleukin (IL)-22 is an inflammatory cytokine discovered in recent years and shows versatile functions; however, its role in PAD remains unknown. Here, we test whether IL-22 and its receptors are involved in angiogenesis in experimental PAD. Both IL-22 and its receptor-IL-22 receptor 1(IL-22R1) were upregulated in muscle and endothelial cells after ischemia. In experimental PAD models, blocking IL-22 using IL-22 monoclonal antibody impaired perfusion recovery and angiogenesis; on the other hand, IL-22 treatment improved perfusion recovery. Ischemic muscle tissue was harvested 3 days after experimental PAD for biochemical test, IL-22 antagonism resulted in decreased Signal Transducer and Activator of Transcription (STAT3) phosphorylation, but did not alter the levels of VEGF-A or cyclic guanine monophosphate (cGMP) levels in ischemic muscle. In cultured endothelial cells, IL-22R1 was upregulated under simulated ischemic conditions, and IL-22 treatment increased STAT3 phosphorylation, endothelial cell survival and tube formation. Knock down of IL-22R1 or treatment with STAT3 inhibitor blunted IL-22-induced endothelial cell survival or tube formation. Ischemia-induced IL-22 and IL-22R1 upregulation improves angiogenesis in PAD by inducing STAT3 phosphorylation in endothelial cells. IL-22R1 may serve as a new therapeutic target for PAD.