Type 1 diabetes pathogenesis: an omics-based investigation using Non-Obese Diabetic (NOD) mice 3624

Description Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing pancreatic β cells. Despite significant advances in understanding T1D pathogenesis, the immunological mechanisms underlying β cell destruction remain incompletely understood. To address this, we employed single-cell RNA sequencing of pancreatic macrophages in T1D-prone non-obese diabetic (NOD) mice at 6-week, 9-week and 21-week stage. The 6-week, 9-week and 21-week time points represent the prediabetic, early diabetic and diabetic stage respectively. Our analysis revealed distinct proinflammatory macrophage cluster, Ccr9+ macrophages, at 21 weeks of age. Chemokine expression was dynamically regulated, as immune cell recruiters Ccl4 and Ccl5 was observed at T1D onset and Ccl8 was prominent during overt diabetes. We extended our analysis to examine the role of oxidative stress in T1D by performing spatial transcriptomics between NOD and NOD.Ncf1m1J mice. NOD.Ncf1m1J mice exhibit a delay in T1D due to their inability to produce NADPH oxidase-derived superoxide. Spatial transcriptomics analysis highlighted an upregulation of Reg genes involved in β-cell regeneration and anti-inflammatory genes, including Mid1 and Erdr1, in NOD.Ncf1m1J mice. Some of our findings, such as the Reg and Mid1 genes, were validated through bulk RNA sequencing and real-time PCR assays. Our findings may provide new insight on immune- and β-cell-specific pathways involved in T1D progression and prevention. Funding Sources Supported by National Institutes of Health grants NIH/NIDDK: DK126456, DK127497, DK131716, DK138469, NSF: 2208831, JDRF: 2-SRA-2024-1509-S-B Topic Categories Computational and Systems Immunology (COMP)