Immunopathology Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.
Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.
Nat Commun. 2024 May 29;15(1):4527. doi: 10.1038/s41467-024-48320-2.
The IL-22RA1 receptor is highly expressed in the pancreas, and exogenous IL-22 has been shown to reduce endoplasmic reticulum and oxidative stress in human pancreatic islets and promote secretion of high-quality insulin from beta-cells. However, the endogenous role of IL-22RA1 signaling on these cells remains unclear. Here, we show that antibody neutralisation of IL-22RA1 in cultured human islets leads to impaired insulin quality and increased cellular stress. Through the generation of mice lacking IL-22ra1 specifically on pancreatic alpha- or beta-cells, we demonstrate that ablation of murine beta-cell IL-22ra1 leads to similar decreases in insulin secretion, quality and islet regeneration, whilst increasing islet cellular stress, inflammation and MHC II expression. These changes in insulin secretion led to impaired glucose tolerance, a finding more pronounced in female animals compared to males. Our findings attribute a regulatory role for endogenous pancreatic beta-cell IL-22ra1 in insulin secretion, islet regeneration, inflammation/cellular stress and appropriate systemic metabolic regulation.
IL-22RA1 受体在胰腺中高度表达，外源性 IL-22 已被证明可减少人胰岛内质网和氧化应激，并促进β细胞分泌高质量的胰岛素。然而，IL-22RA1 信号在内分泌细胞上的内源性作用尚不清楚。在这里，我们表明，在培养的人胰岛中中和 IL-22RA1 的抗体导致胰岛素质量受损和细胞应激增加。通过生成特异性缺乏胰腺α或β细胞 IL-22ra1 的小鼠，我们证明了小鼠β细胞 IL-22ra1 的缺失导致胰岛素分泌、质量和胰岛再生减少，同时增加胰岛细胞应激、炎症和 MHC II 表达。这些胰岛素分泌的变化导致葡萄糖耐量受损，与雄性动物相比，雌性动物的这一发现更为明显。我们的研究结果表明，内源性胰腺β细胞 IL-22RA1 在胰岛素分泌、胰岛再生、炎症/细胞应激和适当的全身代谢调节中起调节作用。
