Introduction and Objective: Cytokines have been suggested as a potential contributing factor in the onset of type 1 diabetes due to their effect on insulin secretion and islet viability. However, our recent work suggests that cytokine signaling in islets may primarily function to protect β-cells by stimulating the expression of antiviral, antibacterial, and antioxidant genes. Given that these studies have been predominantly performed in vitro using isolated islets or purified populations of endocrine cells, the objective of this study was to evaluate the effects of endogenously produced cytokines, especially IL-1, on islet gene expression in vivo. Methods: Low dose (0.33 mg/kg) lipopolysaccharide (LPS) was administered to mice with β-cell-specific deletion of the interleukin-1 type 1 signaling receptor (βIl1r1KO) via IP injection to stimulate in vivo cytokine production. Islets were isolated 6 h later and gene expression was evaluated in islet sub-populations using scRNA-sequencing. Gene and protein expression was confirmed in islets 3-24 h post-LPS administration by qRT-PCR and immunofluorescent imaging. Results: Cytokines, such as IL-1, were detected in the serum within hours of LPS exposure. scRNA-sequencing of islets isolated 6h after LPS administration identified in vivo enrichment of antiviral, antibacterial, and antioxidant genes in β-cells that express IL-1R. Using βIl1r1KO mice, of the 1,500 differentially expressed genes identified, over 1/3 are dependent on IL-1 signaling, even in the presence of other soluble mediators. Functional enrichment analysis of these IL-1 dependent genes shows that antipathogen genes and defense response genes are among the most highly enriched, indicating that IL-1 is a primary mediator of early β-cell responses to immune stimulation in vivo. Conclusion: Our findings provide direct evidence for cross talk between the innate immune and endocrine systems and support our hypothesis that β-cells respond to cytokines by initiating protective cellular responses to reduce their susceptibility to virus-mediated damage. Disclosure J. Bartosiak: None. P. Hansen: None. K. Harty: None. J. Corbett: None.
BARTOSIAK et al. (Fri,) studied this question.