Deputy Director (Research)
Immunity, Infection and Inflammation Program
Mater Research Institute - The University of Queensland
IL-22-mediated suppression of islet inflammation
Mike McGuckin1, Sumaira Z Hasnain1, Danielle J Borg2, Thomas Loudovaris3, Thomas W Kay3, Helen E Thomas3, Jonathon P Whitehead2, Josephine M Forbes2, John B Prins2.
1Immunity, Infection and Inflammation Program, Mater Research Institute - The University of Queensland, Brisbane, Australia; 2Metabolic and Cardiovascular Disease Program, Mater Research Institute - The University of Queensland, Brisbane, Australia; 3Islet Biology Unit, St Vincents Research Institute, Melbourne, Australia
Oxidative and ER stress are features of pancreatic β-cell dysfunction and depletion in both type 1 and type 2 diabetes. In autoimmune diabetes oxidative and ER stress occurs in response to a cytokine storm initiated during insulitis and is thought to be a substantial driver of β-cell apoptosis. In type 2 diabetes β-cell oxidative and ER stress occurs as a result of lower level chronic inflammation and co-exposure to high concentrations of non-esterified fatty acids and glucose. In addition to cytokines already identified as contributing to β-cell stress, we have identified IL-23, IL-24 and IL-33 as significant contributors to β-cell oxidative and ER stress in obesity in mice. The IL-22 cytokine boosts barrier function and wound repair in the skin and mucosae, however its receptor (IL-22R1) is most highly expressed by islet secretory cells. In contrast to IL-23, IL-24 and IL-33, IL-22 down-regulates pro-oxidant genes (particularly Nos2 which encodes induced-nitric oxide synthase) and up-regulates anti-oxidant genes such as Gpx5 (glutathione peroxidase-5), Prdx5 (peroxiredoxin-5), and Sod2 (superoxide dismutase-2) in murine MIN6N8 β-cells and islets, and human islets. Pre-exposure of β-cells or islets to IL-22 provides near complete protection from oxidative stress and ER stress induced by high glucose, non-esterified fatty acids, inflammatory cytokines and environmental reactive oxygen species. IL-22R1 neutralising antibodies induce oxidative and ER stress in healthy mouse and human islets, demonstrating that IL-22-IL-22R1 signalling maintains islet homeostasis. Islets from mice with high fat diet-induced obesity show immune activation, chronic ER stress and hypersecretion of insulin. Ex vivo exposure to IL-22 suppresses ER stress and chemokine production, and reduces glucose-stimulated insulin secretion. Obese mice treated with IL-22 showed normalised random fed blood glucose within 7 days and normal glucose tolerance and fasting insulin by 2 weeks. Islets from IL-22-treated obese mice showed greatly reduced proinsulin secretion and near complete suppression of ER stress and inflammation. Furthermore, islets from mice treated with IL-22 show an improvement in the ability of secreted insulin to drive glucose uptake in cultured adipocytes. Taken together these data suggest that IL-22 is a natural regulator of β-cell insulin biosynthesis and secretion, protecting the β-cell from stress, preventing hypersecretion of poor quality insulin, and suppressing innate islet inflammation. Whether the protective effects of exogenous IL-22 will protect β-cells from the much higher concentrations of inflammatory cytokines found in islets during autoimmune diabetes is yet to be determined. However, the protective effects of IL-22 warrant investigation as an ex vivo-delivered mechanism to reduce stress in islets isolated for transplantation, and as an in vivo-delivered mechanism to protect islets after transplantation.
This is an invited speaker abstract for State-of-the-Art Workshop: Modulating Islet Inflammation.