Emerging roles of Toll-like receptor 9 in cardiometabolic disorders

Abstract

Growing evidence suggests that damage-associated molecule patterns (DAMPs) and their receptors, pattern recognition receptors (PRRs), are associated with the progression of cardiometabolic disorders, including obesity-related insulin resistance and atherosclerosis. Cardiometabolic disorders share sterile chronic inflammation as a major cause; however, the exact mechanisms are still obscure. Toll-like receptor 9 (TLR9), one of the nucleic acid-sensing TLRs, recognizes DNA fragments derived from pathogens and contributes to self-defense by activation of the innate immune system. In addition, previous studies demonstrated that TLR9 recognizes DNA fragments released from host cells, accelerating sterile inflammation, which is associated with inflammatory diseases such as autoimmune diseases. In obese adipose tissue and atherosclerotic vascular tissue, various stresses release DNA fragments and/or nuclear proteins as DAMPs from degenerated adipocytes and vascular cells. Recent studies indicated that the activation of TLR9 in immune cells including macrophages and dendritic cells by recognition of these DAMPs promotes inflammation in these tissues, which causes cardiometabolic disorders. This review discusses recent advances in understanding the role of sterile inflammation associated with TLR9 and its endogenous ligands in cardiometabolic disorders. New insights into innate immunity may provide better understanding of cardiometabolic disorders and new therapeutic options for these major health threats in recent decades.

Keywords: Cardiometabolic disorders; Cell-free DNA; Inflammation; Toll-like receptor 9.

Fig. 1

Overview of TLR signaling. TLRs are classified into cell surface TLRs and intracellular TLRs. Each TLR recognizes their specific ligands and promotes gene expression of inflammatory molecules mainly via NF-κB and IRF pathway in immune cells

Fig. 2

TLR9 signaling in inflammatory diseases. Activation of TLR9 signaling in immune cells leads to release various cytokines and interferons in cardiometabolic organs and other tissues, participating in the pathogenesis of both infectious and sterile inflammatory diseases

Fig. 3

Genetic deletion of TLR9 attenuated obesity-induced adipose tissue inflammation. Representative figures of Mac3 staining of visceral adipose tissue from HFD-fed wild-type or TLR9-deficient mice. Genetic deletion of TLR9 reduced the accumulation of macrophages in adipose tissue, indicating less inflammation. Bar, 100 μm

Fig. 4

Genetic deletion of TLR9 attenuated the development of atherosclerosis. Representative figures of Sudan IV staining of the aortic arch of Ang II-infused Apoe^−/− or Tlr9^−/−Apoe^−/− mice. Genetic deletion of TLR9 attenuated the development of atherosclerosis. Bar, 1 mm

Fig. 5

Role of TLR9 in the development of cardiometabolic disorders. DNA fragments and/or nuclear proteins released from damaged cells/tissues activate immune cells such as macrophages and DCs through TLR9, leading to the development of inflammation in these tissues, which is central in the pathogenesis of cardiometabolic disorders