TRPV1 + Sensory Neurons Control β Cell Stress and Islet Inflammation in Autoimmune Diabetes

• Published in: Cell 2006-12, Vol.127 (6), p.1123-1135
• Main Authors: Razavi, Rozita, Chan, Yin, Afifiyan, F. Nikoo, Liu, Xue Jun, Wan, Xiang, Yantha, Jason, Tsui, Hubert, Tang, Lan, Tsai, Sue, Santamaria, Pere, Driver, John P., Serreze, David, Salter, Michael W., Dosch, H.-Michael
• Format: Article
• Language: English
• Subjects: Animals; Autoimmunity; Capsaicin - pharmacology; Diabetes Mellitus, Type 1 - pathology; Diabetes Mellitus, Type 1 - physiopathology; Female; Inflammation; Insulin Resistance; Insulin-Secreting Cells - pathology; Insulin-Secreting Cells - physiology; Islets of Langerhans - innervation; Islets of Langerhans - pathology; Islets of Langerhans - physiopathology; Male; Mice; Mice, Congenic; Mice, Inbred C57BL; Mice, Inbred NOD; Neurons, Afferent - drug effects; Neurons, Afferent - physiology; Substance P - pharmacology; T-Lymphocytes - immunology; TRPV Cation Channels - genetics; TRPV Cation Channels - physiology
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2006.10.038

In type 1 diabetes, T cell-mediated death of pancreatic β cells produces insulin deficiency. However, what attracts or restricts broadly autoreactive lymphocyte pools to the pancreas remains unclear. We report that TRPV1 + pancreatic sensory neurons control islet inflammation and insulin resistance. Eliminating these neurons in diabetes-prone NOD mice prevents insulitis and diabetes, despite systemic persistence of pathogenic T cell pools. Insulin resistance and β cell stress of prediabetic NOD mice are prevented when TRPV1 + neurons are eliminated. TRPV1 NOD, localized to the Idd4.1 diabetes-risk locus, is a hypofunctional mutant, mediating depressed neurogenic inflammation. Delivering the neuropeptide substance P by intra-arterial injection into the NOD pancreas reverses abnormal insulin resistance, insulitis, and diabetes for weeks. Concordantly, insulin sensitivity is enhanced in trpv1 −/− mice, whereas insulitis/diabetes-resistant NODxB6 Idd4-congenic mice, carrying wild-type TRPV1, show restored TRPV1 function and insulin sensitivity. Our data uncover a fundamental role for insulin-responsive TRPV1 + sensory neurons in β cell function and diabetes pathoetiology.