Type 1 diabetes (T1D) is an autoimmune disease strongly associated with immune cell targeting of pancreatic β-cells, which ultimately produces insulin insufficiency. We identified the Icam1 gene and ICAM-1 protein, which facilitate interaction with immune cells, as elevated in female NOD mice relative to male mice. This observation is consistent with a greater frequency of diabetes onset in female mice in this well-established model of T1D. In addition, ICAM-1 protein abundance was greater in hyperglycemic female NOD compared with age-matched normoglycemic female NOD mice. Upon examining islet β-cell responses to immune cell-derived cytokines, we discovered that the Icam1 gene was rapidly (within 3h) and strongly (> 20-fold) upregulated in mouse, rat, and human islets as well as 832/13 rat insulinoma cells in response to IL-1β (p < 0.01) . Using chromatin immunoprecipitation (ChIP) assays, we identified rapid recruitment (within 30 minutes) of the p65 transcriptional subunit of NF-κB to κB genomic elements within the Icam1 gene promoter (3-fold; p < 0.05 relative to isotype control) . ChIP assays also revealed elevated RNA polymerase II recruitment to the Icam1 gene promoter (within 30 min) in response to IL-1β (7-fold, p < 0.05) . Finally, using single-cell RNA-Sequencing, we discovered that only a few clusters of β-cells expressed Icam1 at very low abundance in the basal (unstimulated) condition, while the majority of β-cell clusters in the IL-1β (3 h) stimulated condition presented with strong Icam1 positive (mRNA expressing) cells. Thus, we conclude that most, if not all, β-cells undergo rapid genetic reprogramming by IL-1β to enhance expression of the Icam1 gene and promote accumulation of the ICAM-1 protein. These findings illustrate the importance of pancreatic β-cell communication with the immune system and reveal inducible events at the β-cell level that are linked with onset and progression of T1D.
T. Martin: None. S. Burke: None. S. Ghosh: None. M. D. Karlstad: None. J. Collier: None.
National Institutes of Health (R03 AI151920-02)