The macrophages in the pancreatic islets are activated and sense pathogen associated products in blood

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Abstract Using RNAseq, we examined the transcriptome of endocrine macrophage in the islets of Langerhans in NOD (non-obese diabetic) and in two non-diabetic controls: NOD.Rag1−/− and B6.g7. The NOD mice spontaneously develop diabetes at 20–24 weeks of age. By gene expression analysis we found that at 3 weeks of age the macrophages from all 3 strains of mice were already activated. They expressed high levels of MHC-II, costimulatory molecules, and the pro-inflammatory cytokines IL-1b, TNF, both at protein and transcript levels. Leveraging the ImmGen database, we found that this activation signature is common for resident macrophages from barrier surfaces of the body, in particular lung and gastrointestinal tract. In addition to the basal level activation found in all islet macrophages at 3 weeks of age, we found an elevated activation signature in NOD when comparing to non-diabetic control. This finding indicates that the diabetic inflammatory process was already underway at as early as 3 weeks of age. These results were confirmed by single cell qRT-PCR that showed a distinct activated population of Cxcl9, Ccl5, Ly6a high (~28%) macrophages in NOD, but not in NOD.Rag1−/−. Additionally, supporting the idea of a barrier phenotype in islet macrophages, we found that they responded to intravenous injection of lipopolysaccharide by rapid upregulation of inflammatory gene expression. In imaging experiments we showed that macrophages were constantly extending filopodias into the blood lumen and capturing microparticles. In conclusion, the islet macrophages are in a highly activated steady state, sense pathogen associated products in blood, and may have a protective barrier function in the endocrine pancreas.