Involvement of Acetylcholine Receptors in Cholinergic Pathway-Mediated Protection Against Autoimmune Diabetes.

Maria J. Fernández-Cabezudo,Ghada Bashir,Junu A. George,Basel K. al-Ramadi,Yassir A. Mohamed,Dietrich E. Lorke,Alreem Al-Mansori,Georg Petroianu,Mohammed M. Qureshi

doi:10.3389/fimmu.2019.01038

Maria J. Fernández-Cabezudo, Ghada Bashir + Show 7 more

Open Access

https://doi.org/10.3389/fimmu.2019.01038

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Abstract

Type I diabetes (T1D) is a T cell-driven autoimmune disease that results in the killing of pancreatic β-cells and, consequently, loss of insulin production. Using the multiple low-dose streptozotocin (MLD-STZ) model of experimental autoimmune diabetes, we previously reported that pretreatment with a specific acetylcholinesterase inhibitor (AChEI), paraoxon, prevented the development of hyperglycemia in C57BL/6 mice. This correlated with an inhibition of T cell infiltration into the pancreatic islets and a reduction in pro-inflammatory cytokines. The cholinergic anti-inflammatory pathway utilizes nicotinic and muscarinic acetylcholine receptors (nAChRs and mAChRs, respectively) expressed on a variety of cell types. In this study, we carried out a comparative analysis of the effect of specific antagonists of nAChRs or mAChRs on the development of autoimmune diabetes. Co-administration of mecamylamine, a non-selective antagonist of nAChRs maintained the protective effect of AChEI on the development of hyperglycemia. In contrast, co-administration of atropine, a non-selective antagonist of mAChRs, mitigated AChEI-mediated protection. Mice pretreated with mecamylamine had an improved response in glucose tolerance test (GTT) than mice pretreated with atropine. These differential effects of nAChR and mAChR antagonists correlated with the extent of islet cell infiltration and with the structure and functionality of the β-cells. Taken together, our data suggest that mAChRs are essential for the protective effect of cholinergic stimulation in autoimmune diabetes.

Highlights

Type 1 diabetes (T1D) is an autoimmune disease characterized by the progressive destruction of the insulin-producing β-cells in the pancreatic islets of Langerhans by autoreactive T cells
When the muscarinic acetylcholine receptor (mAChR) antagonist atropine was co-administered with paraoxon, STZ treatment induced a progressive increase in blood glucose averaging >200 mg/dl by day 28 post-STZ treatment
These elevated levels persisted in 4 out of 6 mice in this group until the end of the observation period (Figure 1; Atropine+acetylcholinesterase inhibitor (AChEI)+STZ group). These results suggest that the mAChRs play an important role in the AChEI-induced protection in this model

Summary

Introduction

Type 1 diabetes (T1D) is an autoimmune disease characterized by the progressive destruction of the insulin-producing β-cells in the pancreatic islets of Langerhans by autoreactive T cells. The development of the disease starts with the β-cell destruction in individuals with genetic pre-disposition and under specific environmental factors, followed by recruitment and activation of Acetylcholine Receptors in Autoimmune Diabetes inflammatory cells (T and B cells, myeloid, and natural killer cells) to the islets leading to insulitis [1, 2]. ACh, in turn, can bind to the nAChRs and mAChRs expressed on pancreatic cells and play a key role in regulating pancreatic metabolic functions including glucose homeostasis [3]. Mice selectively lacking M3 mAChR in pancreatic β-cells have an impaired glucose tolerance and a significantly reduced insulin release. While some studies reported no effect of nAChR agonists on hyperglycemia or β-cell function [17,18,19], other studies showed that the administration of specific α7nAChR agonists reduced hyperglycemia in diabetic animal models [20,21,22]

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