Role of nucleic acid sensing in the pathogenesis of type 1 diabetes.

During infections, nucleic acids of pathogens are also engaged in recognition via several exogenous and cytosolic pattern recognition receptors, such as the toll-like receptors, retinoic acid inducible gene-I-like receptors, and nucleotide-binding and oligomerization domain-like receptors. The binding of the pathogen-derived nucleic acids to their corresponding sensors initiates certain downstream signaling cascades culminating in the release of type-I interferons (IFNs), especially IFN-α and other cytokines to induce proinflammatory responses towards invading pathogens leading to their clearance from the host. Although these sensors are hardwired to recognize pathogen associated molecular patterns, like viral and bacterial nucleic acids, under unusual physiological conditions, such as excessive cellular stress and increased apoptosis, endogenous self-nucleic acids like DNA, RNA, and mitochondrial DNA are also released. The presence of these self-nucleic acids in extranuclear compartments or extracellular spaces or their association with certain proteins sometimes leads to the failure of discriminating mechanisms of nucleic acid sensors leading to proinflammatory responses as seen in autoimmune disorders, like systemic lupus erythematosus, psoriasis and to some extent in type 1 diabetes (T1D). This review discusses the involvement of various nucleic acid sensors in autoimmunity and discusses how aberrant recognition of self-nucleic acids by their sensors activates the innate immune responses during the pathogenesis of T1D.

Butyrate induced Tregs are capable of migration from the GALT to the pancreas to restore immunological tolerance during type-1 diabetes.

Type-1 diabetes (T1D) is an autoimmune disease caused by progressive loss of insulin-producing beta cells in the pancreas. Butyrate is a commensal microbial-derived metabolite, implicated in intestinal homeostasis and immune regulation. Here, we investigated the mechanism of diabetes remission in non-obese diabetic (NOD) mice following butyrate administration. Sodium butyrate (150 mM) was administered to female NOD mice in drinking water after the onset of hyperglycemia (15-25 weeks age) and at 4 weeks of age (early-intervention group). Butyrate administration reduced the progression of hyperglycemia in diabetic mice and delayed onset of diabetes in the early-intervention group with a reduction in insulitis. Butyrate administration increased regulatory T cells (Tregs) in the colon, mesenteric lymph nodes, Peyer's patches, and its protective effects diminished upon depletion of Tregs. Further, an increase in α4ß7, CCR9, and GPR15 expressing Tregs in the pancreatic lymph nodes (PLN) and pancreas in butyrate-treated mice suggested migration of gut-primed Tregs towards the pancreas. Finally, the adoptive transfer experiments demonstrated that induced Tregs from gut-associated lymphoid tissue can migrate towards the pancreas and PLN and delay the onset of diabetes. Our results thus suggest that early administration of butyrate can restore immunological tolerance during T1D via induction of Tregs with migratory capabilities.