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Abstract Objective 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. Methods and results 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. Conculsion 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. Highlights • Interleukin-22 and its receptor (IL22R1) are upregulated after hindlimb ischemia. • Loss of IL-22 by mAb reduced angiogenesis. • IL-22 overexpression improved angiogenesis after hindlimb ischemia. [ABSTRACT FROM AUTHOR]

IL-22 is a unique cytokine that is upregulated in many chronic inflammatory diseases, including asthma, and modulates tissue responses during inflammation. However, the role of IL-22 in the resolution of inflammation and how this contributes to lung repair processes are largely unknown. Here, we tested the hypothesis that IL-22 signaling is critical in inflammation resolution after repetitive exposure to agricultural dust. Using an established mouse model of organic dust extract-induced lung inflammation, we found that IL-22 knockout mice have an enhanced response to agricultural dust as evidenced by an exacerbated increase in infiltrating immune cells and lung pathology as compared to wild-type controls. We further identified that, in response to dust, IL-22 is expressed in airway epithelium and in Ym1+ macrophages found within the parenchyma in response to dust. The increase in IL-22 expression was accompanied by increases in IL-22 receptor IL-22R1 within the lung epithelium. In addition, we found that alveolar macrophages in vivo as well as THP-1 cells in vitro express IL-22, and this expression is modulated by dust exposure. Furthermore, subcellular localization of IL-22 appears to be in the Golgi of resting THP1 human monocytes, and treatment with dust extracts is associated with IL-22 release into the cytosolic compartment from the Golgi reservoirs during dust extract exposure. Taken together, we have identified a significant role for macrophage-mediated IL-22 signaling that is activated in dust-induced lung inflammation in mice. • IL-22 regulates lung inflammation in a mouse model of organic dust exposure. • YM1+ macrophages in the lung produce IL-22. • IL-22 knockout leads to exacerbated organic dust-induced lung pathology. • Lung reparative responses following dust exposure are regulated by IL-22. [ABSTRACT FROM AUTHOR]