Cardiovascular diseases
Targeting innate immunity for CV benefit

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The initiation and progression of vascular inflammation are driven by the retention of cholesterol in the artery wall, where its modification by oxidation and/or enzymes triggers the innate immune host response. Although previously considered a broad, primitive defense mechanism against invading pathogens, it has become clear that pattern recognition receptors of the innate immune system can cooperate to precisely regulate signaling pathways essential for the proper initiation of both innate and acquired immunity. Recent evidence suggests that these pattern recognition receptors may orchestrate the host response to modified endogenous ligands involved in sterile chronic inflammatory syndromes, including atherosclerosis. In this review, we will summarize the current understanding of innate immune receptors and the putative ligands that regulate the numerous responses that promote this disease, including monocyte recruitment, macrophage cholesterol uptake, and pro-inflammatory signaling cascades. Specific emphasis will be placed on the potential of these innate immune targets for therapeutic interventions to retard the progression of atherosclerosis or to induce its regression.

Section editors:

Colin H. Macphee – Department of Vascular Biology, GlaxoSmithKline, King of Prussia, PA, USA

Alan Daugherty – Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA

Section snippets

Monocyte/macrophages

The macrophage, a major cellular effector of the innate immune response, is the predominant cell type in the early atherosclerotic lesion. This gives the macrophage a unique and primal role in the development and progression of atherosclerosis. Macrophages recognize and internalize modified lipoproteins leading to cellular cholesterol accumulation. Although initially beneficial, this protective response appears to become overwhelmed, leading to massive cellular cholesterol accumulation and the

Monocyte recruitment and innate immune targets

Central to the development of atherosclerotic lesions is the influx of monocytes into the arterial intima and the initiation of a chronic inflammatory milieu that drives plaque formation. Whereas monocyte recruitment is often cited as an early event in atherosclerosis, and therefore not considered an ideal target for the development of therapeutics in humans with established disease, it is very likely that monocyte ingress and egress are dynamic processes that actively contribute to lesion

Scavenger receptors

The conversion of subendothelial macrophages into cholesterol-laden foam cells is believed to constitute the foundation of the atherosclerotic lesion. Native LDL has traditionally not been considered capable of generating foam cells because cells downregulate their LDL receptor number with increasing cellular cholesterol content, precluding lipid loading via this pathway [9]. Modification of LDL is therefore required to drive lipid uptake by alternative receptor pathways. Over the past thirty

Scavenger receptor A

SRA was the first member of the scavenger receptor family to be molecularly identified and is expressed in monocytes/macrophages, smooth muscle and endothelial cells [17]. The role of SR-A in atherogenesis is currently controversial, as conflicting results have emerged from different groups studying the effect of targeted deletion and overexpression of SRA in multiple mouse models of atherosclerosis. Initial studies of SR-A deletion in the Apoe−/− mouse model on a hybrid background of ICR/129

CD36

CD36 is a member of the B class of the scavenger receptor family and unlike SRA, this receptor is widely expressed on monocytes/macrophages, adipocytes, microvascular endothelium, platelets, and erythroid precursors (reviewed in [12]). CD36 binds a diverse group of ligands that can contribute to atherosclerotic processes including endogenous ligands such as thrombospondin-1, collagen and fatty acids, as well as modified endogenous ligands such as oxidized LDL and apoptotic cells [12]. In

CXCL16/SR-PSOX

The scavenger receptor CXCL16, also known as SR-PSOX, is unique in that it combines scavenger receptor functions with the properties of an inflammatory chemokine (reviewed in [12]). Membrane bound CXCL16 is composed of a glycosylated mucin stalk fused to a chemokine domain that attracts cells expressing the receptor CXCR6 and also mediates the internalization of oxLDL, bacteria and apoptotic cells. The extracellular domain of CXCL16 also undergoes proteolytic cleavage generating a soluble

Toll-like receptors

Over the past decade the essential role of the Toll-like receptors in innate immune sensing of pathogens has become apparent (reviewed in [37]). This family of mammalian pattern recognition receptors has 11 members that act as homo- or hetero-dimers to recognize invariant patterns expressed on pathogens, including bacterial cell wall components and pathogen derived nucleotides. TLRs fall into two broad classes – the cell surface TLRs; TLR1/2/4/5/6 and the endosomal TLRs TLR3/7/8/9 (Fig. 2). The

Toll-like receptors as targets of inflammatory signaling pathways

Under normal conditions, endothelial cells express low levels of TLRs where these receptors perform innate immune surveillance. However, expression of TLR1, TLR2, TLR4 and TLR6 is markedly upregulated by endothelial cells and macrophages in atherosclerotic arteries suggesting a role for these TLRs in the initiation and/or maintenance of vascular inflammation [44]. Targeted deletion of MyD88, a key signaling adaptor for all TLRs except TLR3, provided the first genetic evidence of a role for

Therapeutic challenges in targeting innate immune pathways for atherosclerosis

Although the evidence implicating the activation of innate immunity pathways in atherosclerosis is strong, the challenges of creating new therapeutics directed at these pathways are formidable. The role of innate immunity in protecting against microbial pathogens raises the specter of rendering hosts susceptible to a multitude of infectious agents when these pathways are interrupted for therapeutic benefit. Many of the mice that have been genetically engineered to lack components of the innate

Conclusion

A growing body of basic science has implicated innate immunity pathways in the development and progression of atherosclerosis. These pathways result in the establishment of a sterile, chronic inflammation in the artery wall that ultimately leads to the narrowing of the arterial lumen and the subsequent rupture of plaques, which are the critical pathophysiological underpinnings of clinical coronary artery disease events. Our knowledge of the receptors involved in innate immunity and their

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