Pancreatic β-Cells Limit Autoimmune Diabetes via an Immunoregulatory Antimicrobial Peptide Expressed under the Influence of the Gut Microbiota

Antimicrobial peptides (AMPs) expressed by epithelial and immune cells are largely described for the defense against invading microorganisms. Recently, their immunomodulatory functions have been highlighted in various contexts. However how AMPs expressed by non-immune cells might influence autoimmune responses in peripheral tissues, such as the pancreas, is unknown. Here, we found that insulin-secreting β-cells produced the cathelicidin related antimicrobial peptide (CRAMP) and that this production was defective in non-obese diabetic (NOD) mice. CRAMP administrated to prediabetic NOD mice induced regulatory immune cells in the pancreatic islets, dampening the incidence of autoimmune diabetes. Additional investigation revealed that the production of CRAMP by β-cells was controlled by short-chain fatty acids produced by the gut microbiota. Accordingly, gut microbiota manipulations in NOD mice modulated CRAMP production and inflammation in the pancreatic islets, revealing that the gut microbiota directly shape the pancreatic immune environment and autoimmune diabetes development. [Display omitted] •Pancreatic β-cells express the cathelicidin-related antimicrobial peptide (CRAMP)•CRAMP is protective in the adult NOD mice, a model for type 1 diabetes•CRAMP converts inflammatory into regulatory immune cells in the pancreas•The gut microbiota via short-chain fatty acids governs CRAMP production by β-cells It is unclear to what extent antimicrobial peptides expressed by epithelial cells influence immunity in peripheral tissues. Diana and colleagues show that the gut microbiota via short-chain fatty acids promote antimicrobial peptide CRAMP expression in pancreatic α- and β-cells, which protects against autoimmune diabetes in NOD mice