IL18 signaling causes islet β cell development and insulin secretion via different receptors on acinar and β cells

Dev Cell. 2022 Jun 20;57(12):1496-1511.e6. doi: 10.1016/j.devcel.2022.05.013. Epub 2022 Jun 7.


Diabetic patients show elevated plasma IL18 concentrations. IL18 has two receptors: the IL18 receptor (IL18r) and the Na-Cl co-transporter (NCC). Here, we report that IL18 is expressed on islet α cells, NCC on β cells, and IL18r on acinar cells in human and mouse pancreases. The deficiency of these receptors reduces islet size, β cell proliferation, and insulin secretion but increases β cell apoptosis and exocrine macrophage accumulation after diet-induced glucose intolerance or streptozotocin-induced hyperglycemia. Together with the glucagon-like peptide-1 (GLP1), IL18 uses the NCC and GLP1 receptors on β cells to trigger β cell development and insulin secretion. IL18 also uses the IL18r on acinar cells to block hyperglycemic pancreas macrophage expansion. The β cell-selective depletion of the NCC or acinar-cell-selective IL18r depletion reduces glucose tolerance and insulin sensitivity with impaired β cell proliferation, enhanced β cell apoptosis and macrophage expansion, and inflammation in mouse hyperglycemic pancreas. IL18 uses NCC, GLP1r, and IL18r to maintain islet β cell function and homeostasis.

Keywords: GLP1; GLP1 receptor; IL18; IL18 receptor; Na-Cl co-transporter; acinar cells; endocrine; exocrine; α cells; β cells.

MeSH terms

  • Animals
  • Glucagon-Like Peptide 1 / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells* / metabolism
  • Interleukin-18* / metabolism
  • Mice
  • Pancreas* / cytology
  • Pancreas* / metabolism


  • IL18 protein, human
  • Insulin
  • Interleukin-18
  • Glucagon-Like Peptide 1