Pancreatic beta-cell IL-22 receptor deficiency induces age-dependent dysregulation of insulin biosynthesis and systemic glucose homeostasis

Haressh Sajiir, Kuan Yau Wong, Alexandra Müller, Sahar Keshvari, Lucy Burr, Elena Aiello, Teresa Mezza, Andrea Giaccari, Guido Sebastiani, Francesco Dotta, Grant A. Ramm, Graeme A. Macdonald, Michael A. McGuckin, Johannes B. Prins and Sumaira Z. Hasnain ()
Additional contact information
Haressh Sajiir: Translational Research Institute
Kuan Yau Wong: Translational Research Institute
Alexandra Müller: Translational Research Institute
Sahar Keshvari: Translational Research Institute
Lucy Burr: Translational Research Institute
Elena Aiello: University of Siena
Teresa Mezza: Università Cattolica del Sacro Cuore
Andrea Giaccari: Università Cattolica del Sacro Cuore
Guido Sebastiani: University of Siena
Francesco Dotta: University of Siena
Grant A. Ramm: The University of Queensland
Graeme A. Macdonald: The University of Queensland
Michael A. McGuckin: University of Melbourne
Johannes B. Prins: Royal Brisbane and Women’s Hospital
Sumaira Z. Hasnain: Translational Research Institute

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-48320-2

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