Introduction and Objective: It has been suggested that infection may contribute to T1D development via extended exposure of islets to proinflammatory cytokines. Recent evidence, however, suggests that the primary effects of cytokine signaling in islets may be protective through the upregulation of antipathogen and antioxidant genes in β-cells. This study tests the hypothesis that there is an immune and endocrine axis in which endogenously produced cytokines function to initiate physiological islet responses and enhance β-cell fitness.Methods: Low dose (0.33 mg/kg) LPS was administered by IP injection to C57BL/6J mice. Serum cytokines were measured, and islets were isolated 3-24h later. Gene expression was evaluated in islet sub-populations using scRNA-seq with Seurat analysis and confirmed in islets by qRT-PCR. Protein expression was evaluated by immunofluorescent imaging of pancreatic sections.Results: Low dose LPS administration in mice stimulates the transient production of proinflammatory cytokines such as IL-1β that peak in the serum within 4-8h. Antipathogen genes are among the most highly upregulated genes in β-cells isolated from mice 6h after LPS-initiated immune stimulation as assessed by scRNA-seq. qRT-PCR of islets isolated from these animals show expression of these genes peaks within 3-6h of LPS administration and immunofluorescent imaging shows upregulation of protein expression for several representative antiviral genes. Additionally, β-cell identity genes are repressed within 6h of LPS administration. By 24h post-LPS administration, both antipathogen and islet identity gene expression return to baseline. Using LPS administration in mice with β-cell-specific deletion of the interleukin-1 type 1 signaling receptor (Il1r1), we’ve identified IL-1 as a key mediator of early β-cell responses to immune stimulation in vivo.Conclusion: These studies define a new model for studying the connection between the immune and endocrine systems and support our hypothesis that this interaction functions to enhance the fitness of islet endocrine cells.
J. Bartosiak: None. K. Harty: None. E. Schumacher: None. P. Hansen: None. J.A. Corbett: None.
National Institutes of Health (AI2212769)
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