VASCULAR INFLAMMATION AND ATHEROGENESIS ARE ACTIVATED VIA RECEPTORS FOR PAMPs AND SUPPRESSED BY REGULATORY T CELLS

Abstract

Despite significant advances in identifying the risk factors and elucidating atherosclerotic pathology, atherosclerosis remains the leading cause of morbidity and mortality in industrialized society. These risk factors independently or synergistically lead to chronic vascular inflammation, which is an essential requirement for the progression of atherosclerosis in patients. However, the mechanisms underlying the pathogenic link between the risk factors and atherosclerotic inflammation remain poorly defined. Significant progress has been made in two major areas, which are determination of the roles of the receptors for pathogen-associated molecular patterns (PAMPs) in initiation of vascular inflammation and atherosclerosis, and characterization of the roles of regulatory T cells in suppression of vascular inflammation and atherosclerosis. In this review, we focus on three related issues: (1) examining the recent progress in endothelial cell pathology, inflammation and their roles in atherosclerosis; (2) analyzing the roles of the receptors for pathogen-associated molecular patterns (PAMPs) in initiation of vascular inflammation and atherosclerosis; and (3) analyzing the advances in our understanding of suppression of vascular inflammation and atherosclerosis by regulatory T cells. Continuous improvement of our understanding of the risk factors involved in initiation and promotion of artherogenesis, will lead to the development of novel therapeutics for ischemic stroke and cardiovascular diseases.

Fig. 1

Vascular inflammation and atherosclerosis are activated via receptors for PAMPs and suppressed by regulatory T cells.

Fig. 2. TLRs and NLRs signaling pathways in the generation of proinflammatory cytokines IL-1β and IL-18

Abbreviations: ASC, apoptosis-associated speck-like protein containing a CARD; CARD domain, caspase recruitment domain; FIIND, F-interacting domain of Cardinal protein; HMGB1, High mobility group box 1; Hsp60, heat shock protein 60; IRAK4 and IRAK1, IL-1 receptor (IL-1R)–associated kinases 4 and 1; IL-1β, interleukin-1β; LDL, low density lipoproteins; LPS, lipopolysaccharides; MSU, monosodium urate; MyD88, Myeloid differentiation primary response gene (88); NACHT domain, a 300 to 400 residue predicted nucleoside triphosphatase (NTPase) domain present in NAIP, CIITA, HETA and TP1; NALP, NACHT domain, LRR domain, and pyrin domain- containing protein; NF-κB, nuclear factor-κB; NLRs, Nod-like receptors; P2X7, a purinergic receptor; PYD, pyrin domain; R837 and R848, imidazoquinoline compounds that serve as inflammasome activating agents and TLR7 and TLR8 agonists; TLRs, toll-like receptors; TRAF6, TNF receptor-associated factor 6; UV, Ultraviolet light.

Fig. 3

Interaction between agonists/antagonists with TLRs can either enhance or inhibit functions of Tregs and immunosuppressive cytokines, which leads to inhibition or enhancement of inflammation and autoimmune reactions. TLR: toll-like receptor.