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

• Published in: Developmental cell 2022-06, Vol.57 (12), p.1496-1511.e6
• Main Authors: Zhang, Xian, Luo, Songyuan, Wang, Minjie, Huang, Qin, Fang, Wenqian, Li, Jie, Liu, Tianxiao, Zhang, Yuanyuan, Deng, Zhiyong, Liu, Cong-Lin, Guan, Shuling, Ayala, Julio E., Flavell, Richard A., Kulkarni, Rohit N., Libby, Peter, Guo, Junli, Liu, Zhangsuo, Shi, Guo-Ping
• Format: Article
• Language: English
• Subjects: acinar cells; Animals; endocrine; exocrine; GLP1; GLP1 receptor; Glucagon-Like Peptide 1 - metabolism; Humans; IL18; IL18 receptor; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - metabolism; Interleukin-18 - metabolism; Mice; Na-Cl co-transporter; Pancreas - cytology; Pancreas - metabolism; α cells; β cells
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2022.05.013

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. [Display omitted] •α cells, acinar cells, and β cells express IL18, IL18r, and NCC, respectively•NCC-driven IL18 activation of β cells requires GLP1 and the GLP1 receptor•IL18 action on acinar cell IL18r controls pancreas exocrine tissue inflammation•Selective depletion of β cell NCC or acinar cell IL18r exacerbates diabetes Zhang et al. demonstrate that IL18 and GLP1 bind to both the Na-Cl co-transporter and GLP1 receptors on islet β cells, controlling β cell apoptosis, proliferation, and insulin secretion. IL18 activates acinar cells via the IL18 receptor, regulating hyperglycemic exocrine and endocrine inflammation and islet β cell function and homeostasis.