The role of alpha-7 nicotinic acetylcholine receptor in controlling islet inflammation

Islet inflammation is an important pathophysiology in diabetes.  A high-fat diet contributes to this process, increasing peripheral inflammation.  This includes the islet itself, which produces cytokines in response to metabolic insults.  Medical therapies designed to block diabetes associated inflammation increase insulin secretion and reduce insulin resistance.  Our research objective is to explore the activation of endogenous anti-inflammatory signals as targets of therapy.  Once such system is the cholinergic anti-inflammatory pathway modulated by the alpha 7 nicotinic acetylcholine receptor (CHRNA7).  Agonists of this receptor are known to reduce local tissue inflammation in several tissues, but no such role is yet defined in the pancreatic islet. Here, we explore the role of CHRNA7 in the islet’s inflammatory response to a high-fat diet using both islet isolation studies and in vivo experiments with a CHRNA7 KO murine model. 

Islet RNA was isolated from C57BL/6 mice, CHRNA7 KO mice and Japanese macaques and analyzed by RTPCR using species-specific primers for CHRNA7.  Isolated islets from control mice were cultured overnight in 33mM glucose with or without nicotine.  RNA was extracted as above and expression of IL-6 was determined using qPCR.  Islets from wild-type and CHRNA7 KO mice on control or high-fat diet were isolated and cultured for four hours with or without 5ng/mL of LPS.  RNA was extracted and expression of IκBα was assessed by qPCR.   

Our preliminary data demonstrates the expression of CHRNA7 in isolated murine islets as well as the primate’s, providing a translational link to humans.  Exposure of islets to high glucose results in up-relation of IL-6 and this effect is blocked by the agonist nicotine (p<0.05;by 2-Way ANOVA). Islets from CHRNA7 KO male mice on high-fat diet have higher levels of IκBα, a marker of NFκB activation and cytokine production, compared to wild-type mice on the same diet (p<0.01;by 2-Way ANOVA). 

We conclude there is evidence of CHRNA7 expression in islets and when activated results in decreased expression of islet cytokine production.   Ongoing experiments are examining the effects of agonist treatment in KO mice and isolated islets from the same model.  We are also employing several IHC and in situ techniques to determine the specific cell type in which CHRNA7 is expressed.