Oral Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

A novel role for endogenous IL-22/IL22RA1 signaling in the liver-pancreatic β-cell axis (#97)

Haressh Sajiir 1 2 , Sahar Keshvari 1 2 , Kuan Yau Wong 1 2 , Amelia Fotheringham 1 2 , Ran Wang 1 2 , Percival Wiid 1 2 , Jack Lockett 3 4 , Grant Ramm 5 , Graeme Macdonald 4 , John Prins 6 , Michael A. McGuckin 6 , Sumaira Z. Hasnain 1 2 7
  1. Mater Research Institute, Woolloongabba, QLD, Australia
  2. Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia
  3. Mater Research Institute, Translational Research Instutute, Brisbane, Queensland, Australia
  4. Princess Alexandra Hospital, Brisbane, Queensland, Australia
  5. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  6. University of Melbourne, Melbourne, Victoria, Australia
  7. Australian Infectious Diseases Research Centre, Brisbane, Queensland, Australia

The IL-22 receptor, IL-22RA1, is known to be expressed on metabolic tissue, with the highest expression in the pancreas. We had previously discovered that exogenous IL-22 treatment is highly efficacious in metabolic disease [1]. By facilitating the secretion of high quality insulin, exogenous IL-22 treatment resulted in benefits including: complete restoration of glucose tolerance, suppression of fasting hyperinsulinemia/hyperproinsulinemia, and restoration of insulin sensitivity. However, the role of endogenous pancreatic IL-22RA1 signaling in maintaining metabolic homeostasis remained unknown. To understand the role of endogenous IL-22RA1 signaling in pancreatic β-cells, we generated tissue specific IL-22RA1 knockout mice lacking the receptor in pancreatic β-cells (IL-22RA1-/- Ins2Cre) and challenged them with a high fat diet. As the IL-22RA1-/-Ins2Cre mice aged, they had impaired glucose tolerance compared to littermate control animals, and this was exacerbated when the mice were challenged with a high fat diet. Our data demonstrates the importance of endogenous IL-22 in the pancreas as the ablation of pancreatic β-cell IL-22RA1 signaling resulted in reduced insulin biosynthesis in the 20-week-old animals. The liver is a major organ in the control of glucose homeostasis, and was examined in order to evaluate its role in the metabolic phenotype observed. IL-22RA1-/- Ins2Cre animals had decreased hepatic expression of the insulin-regulated lipogenic marker Srebp1-c, and the glucose transporter Glut-2. This was accompanied by increased hepatic expression of inflammatory cytokines (Tnfa, Il1b, Il10, Ccl2) and cellular stress (Nos2, Grp78). Taken together, our data indicates that IL-22RA1 signaling in pancreatic beta cells is hepatoprotective and plays an essential role in insulin-mediated glucose metabolism.

 

  1. Hasnain, S.Z., et al., Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress. Nat Med, 2014. 20(12): p. 1417-26