Metainflammation in Diabetic Coronary Artery Disease: Emerging Role of Innate and Adaptive Immune Responses

Hindawi Publishing Corporation Journal of Diabetes Research Volume 2016, Article ID 6264149, 10 pages http://dx.doi.org/10.1155/2016/6264149 Review Article Metainflammation in Diabetic Coronary Artery Disease: Emerging Role of Innate and Adaptive Immune Responses Vivekanandhan Aravindhan1 and Haridoss Madhumitha2 1 Department of Genetics, Dr. ALM. PG. IBMS, University of Madras, Chennai 600113, India AU-KBC Research Centre, MIT Campus of Anna University, Chennai 600044, India 2 Correspondence should be addressed to Vivekanandhan Aravindhan; Received 19 May 2016; Accepted 19 July 2016 Academic Editor: Zhenwu Zhuang Copyright © 2016 V. Aravindhan and H. Madhumitha. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Globally, noncommunicable chronic diseases such as Type-2 Diabetes Mellitus (T2DM) and Coronary Artery Disease (CAD) are posing a major threat to the world. T2DM is known to potentiate CAD which had led to the coining of a new clinical entity named diabetic CAD (DM-CAD), leading to excessive morbidity and mortality. The synergistic interaction between these two comorbidities is through sterile inflammation which is now being addressed as metabolic inflammation or metainflammation, which plays a pivotal role during both early and late stages of T2DM and also serves as a link between T2DM and CAD. This review summarises the current concepts on the role played by both innate and adaptive immune responses in setting up metainflammation in DM-CAD. More specifically, the role played by innate pattern recognition receptors (PRRs) like Toll-like receptors (TLRs), NOD1-like receptors (NLRs), Rig-1-like receptors (RLRs), and C-type lectin like receptors (CLRs) and metabolic endotoxemia in fuelling metainflammation in DM-CAD would be discussed. Further, the role played by adaptive immune cells (Th1, Th2, Th17, and Th9 cells) in fuelling metainflammation in DM-CAD will also be discussed. 1. Introduction In recent years, noncommunicable chronic diseases such as Type-2 Diabetes Mellitus (T2DM) and Coronary Artery Disease (CAD) are posing a major threat to the world irrespective of geographical and ethnic boundaries [1]. T2DM is known to potentiate CAD which had led to the coining of a new clinical entity named diabetic CAD (DM-CAD), leading to excessive morbidity and mortality [1]. The synergistic interaction between these two comorbidities is through sterile inflammation which is now being addressed as metabolic inflammation or metainflammation [2]. Metainflammation is due to the dysfunction of the immune system which acts like a double edged sword: at optimal level it confers protection against pathogens; at the suboptimal level it leads to immunodeficiency; at supraoptimal level it leads to inflammation. The pathogenesis of DM-CAD is complex with the involvement of multiple factors including genetic predisposition and various environmental factors like high fat diet, sedentary life style, and chronic stress [1]. Though the association of inflammation with T2DM and CAD was envisioned as early as in 1800s the mechanisms mediating these inflammatory responses were not clearly known [3]. T2DM arises due to insulin resistance (IR) during early stages, which in turn arises due to the inflammation of the insulin target organs (adipose, skeletal muscle, and liver) [4]. IR leads to increased insulin demand and thereby causes rapid exhaustion of pancreatic beta cells due to overproduction, eventually leading to insulin deficiency (ID) [4]. Thus, late stage of T2DM is characterized by combined ID and IR leading to hyperglycemia, eventually leading to endothelial dysfunction [5]. CAD is a macrovascular complication characterized by enhanced extravasation and accumulation of inflamed macrophages under the tunica intima, wherein they engulf the oxidized lipids and become foam cells, leading to the formation of atherosclerotic plaques (atherogenesis) [5]. There are 4 important mechanisms that majorly contribute to the development of hyperglycemia induced cardiovascular damage: (1) increased sorbitol production due to activation of polyol pathway, (2) increased O-GlcNAcylation of cytosolic proteins, (3) activation of protein kinase C, 2 and (4) increased formation of Advanced Glycation EndProduct (AGE) [6]. The underlying common element in all these mechanisms is the increased production of reactive oxygen species (ROS) in endothelial cells under diabetic condition [6]. Recently redox stress has also been linked to neoangiogenesis as seen in microvascular complications (HIF-1𝛼 activation) and metainflammation (NF-𝜅B activation) [6]. DM induced hyperglycemia accelerates the process of atherosclerosis, with greater infiltration of inflammatory macrophages and T lymphocytes and increased inflammation of the coronary artery [7]. Metainflammation augments atherogenesis by directly promoting arterial lipid deposition and inducing the proliferation and migration of smooth muscle cells [7]. It also indirectly promotes atherogenesis by augmenting other risk factors of CAD including dyslipidemia, diabetes, and hypertension [6, 7]. Thus there are several immune factors involved in atherosclerosis which involve cells (endothelial cells, macrophages, and lymphocytes), cytokines, chemokines, acute phase proteins, and adhesion molecules [8–10]. Among these C-reactive protein (CRP), Interleukin-6 (IL-6), and Tumour Necrosis Factor (TNF-𝛼) have been used as predictive markers of CAD as evidenced by various epidemiological studies [10]. Thus, metainflammation plays a pivotal role during both early and late stages of T2DM and also serves as a link between T2DM and CAD. However, the exact mechanism behind the initiation of inflammation as seen in these two conditions is not clearly known. In this review, a summary of the role played by innate and adaptive immune responses in setting up metainflammation in DM-CAD would be presented. 2. Role of Innate Metainflammation in DM-CAD The innate immune system serves as a first-line defense mechanism against invading pathogens. Unfortunately, the same system also serves as the first-line initiator of metainflammation in DM-CAD. The pattern recognition receptors (PRRs) which include Toll-like receptors (TLRs), NODlike receptors (NLRs), Rig-1-like receptors (RLRs), and Ctype lectin like receptors (CLRs) serve as the major arsenal of innate immunity in detecting unique pathogen associated molecular patterns (PAMPs) and thereby alerting the immune system [11] (Figure 1). However, apart from these well characterized receptors, new members are being added to this ever increasing list. These receptors are widely distributed in immune and nonimmune cells to enable rapid detection of pathogens and immediate activation of the immune system (danger-signal hypothesis), resulting in immunity. In fact, these (...truncated)