TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes.
In type 1 diabetes, T cell-mediated death of pancreatic beta 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 beta 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 NODxB6Idd4-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 beta cell function and diabetes pathoetiology.
Razavi
Rozita
R
Neurosciences and Mental Health Program, The Hospital for Sick Children, Research Institute, University of Toronto, Toronto, ON, Canada, M5G 1X8.
Chan
Yin
Y
Afifiyan
F Nikoo
FN
Liu
Xue Jun
XJ
Wan
Xiang
X
Yantha
Jason
J
Tsui
Hubert
H
Tang
Lan
L
Tsai
Sue
S
Santamaria
Pere
P
Driver
John P
JP
Serreze
David
D
Salter
Michael W
MW
Dosch
H-Michael
HM
D000818:Animals; D015551:Autoimmunity; D002211:Capsaicin / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D007249:Inflammation; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000473:pathology / Q000502:physiology*; D007515:Islets of Langerhans / Q000294:innervation* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology*; D013373:Substance P / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology; D050916:TRPV Cation Channels / Q000235:genetics / Q000502:physiology*
D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D013373:Substance P; D002211:Capsaicin