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

Abstract

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.

Figure 1

Role of innate immune response in triggering metainflammation associated with DM-CAD. Pattern recognition receptors (PRRs) are the well characterized innate immune receptors which trigger metainflammation following recognition of both pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs). Viral nucleic acids, endotoxins, and peptidoglycans are some of the PAMPS which are released into the circulation following metabolic endotoxemia. Free fatty acids and self-nucleoproteins are some of the endogenous ligands which act as DAMPs. The end result is the activation of NF-κB and IRFs which in turn activate proinflammatory cytokines and type-1 interferons, respectively. These inflammatory mediators destroy pancreatic beta cells leading to insulin deficiency and induce inflammation at insulin target organs leading to insulin resistance (IR) eventually precipitating in Type-2 Diabetes. Long standing diabetes induces systemic inflammation leading to monocyte activation and endothelial dysfunction leading to the extravasation of monocytes and formation of atherosclerotic plaques.

Figure 2

Role of adaptive immune response in triggering metainflammation associated with DM-CAD. CD4⁺T-helper cells are the most well characterized work horses of the adaptive immune system which trigger metainflammation. Inflammation triggered by PRRs is translated to T cells by the APC-T cell interaction which results in the recruitment of these activated cells into pancreases, adipose, liver, and skeletal muscle reinforcing the metainflammation set by PRRs. Depending upon the relative proportions of these cell types pancreatic beta cell apoptosis and IR in insulin target tissues can get aggravated precipitating in Type-2 Diabetes. Long standing diabetes induces systemic inflammation leading to monocyte activation and endothelial dysfunction leading to the extravasation of monocytes and formation of atherosclerotic plaques.