Abstract
Although it is well-established how nutrients, growth factors, and hormones impact functional β-cell mass (BCM), the influence of the central nervous system in this regard, and especially in the context of islet immune modulation, has been understudied. Here we investigated the expression and activity of pancreatic islet α7 nicotinic acetylcholine receptor (α7nAChR) in islet anti-inflammatory and prosurvival signaling. Systemic administration of α7nAChR agonists in mice improved glucose tolerance and curtailed streptozotocin-induced hyperglycemia by retaining BCM, in part through maintaining Pdx1 and MafA expression and reducing apoptosis. α7nAChR activation of mouse islets ex vivo led to reduced inflammatory drive through a JAK2-STAT3 pathway that couples with CREB/Irs2/Akt survival signaling. Because the vagus nerve conveys anti-inflammatory signals to immune cells of the spleen and other nonneural tissues in the viscera by activating α7nAChR agonists, our study suggests a novel role for β-cell α7nAChR that functions to maintain β-cell survival and mass homeostasis through modulating islet cytokine and phosphatidylinositol 3-kinase-dependent signaling pathways. Exploiting these pathways may have therapeutic potential for the treatment of autoimmune diabetes.
Highlights
It is well-established how nutrients, growth factors, and hormones impact functional -cell mass (BCM), the influence of the central nervous system in this regard, and especially in the context of islet immune modulation, has been understudied
The role of the cholinergic branch of the autonomic nervous system (ANS) on -cell function in human islets has been questioned in a study that found that ␣-cells impact -cell function through paracrine secretion of ACh [13], a subsequent study suggests that autonomic signaling through nicotinic receptors B2 and B4 plays an important role in insulin secretion [14]
Data are mounting on the primacy of autonomic failure [5, 6, 31], including early islet nerve loss [32, 33], in the progression of inflammatory cascades leading to autoimmune diabetes
Summary
T1D, type 1 diabetes; ANS, autonomic nervous system; BCM, -cell mass; ACh, acetylcholine; ␣7nAChR or ␣7R, ␣7 nicotinic acetylcholine receptor; iNOS, inducible nitric-oxide synthase; M3R, muscarinic receptor 3; STZ, streptozotocin; MLDS, multiple low-dose STZ; PNU, PNU-282987; KD, knockdown; MLA, methyllycaconitine; Het, haplodeficient; CREB, cAMP-responsive element– binding protein.; Veh, vehicle; i.p., intraperitoneal; IPGTT, intraperitoneal glucose tolerance test; TUNEL, deoxynucleotidyltransferase-mediated dUTP nick end labeling. We further tested the anti-inflammatory effects of ␣7R agonist–mediated activation of STAT3 signaling in islets subjected to a proinflammatory cytokine challenge by pretreatment (1 h) with the PNU agonist or a specific antagonist, methyllycaconitine (MLA) (100 nM), comparing it to vehicle (DMSO)-treated controls. These treatments either increased or decreased STAT3 phosphorylation, respectively, leading to reduced or enhanced NF-B proinflammatory signaling (Fig. 2B). That key transcription factors controlling -cell functional maturation (Pdx and MafA) and survival (Pdx and to a lesser extent CREB) are up-regulated following MLDS induction preceded by ␣7R agonist treatment
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