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Seminal research over the past 20 years has revealed atherosclerosis to be a chronic inflammatory process that shares features with traditional inflammatory diseases including rheumatoid arthritis. More recently, emphasis has been placed on the role of innate immunity in the development and progression of atherosclerosis. In particular, pattern recognition receptors, including Toll-like receptors (TLRs), have been the focus of much attention as modulators of atherogenesis. This review provides an update on the developments in this area of research in the past 2 years, with a specific focus on the current controversies and how these may affect the design of therapeutics. Specifically, we will address the recent evidence that TLRs elicit both protective and detrimental effects in atherosclerosis and the emerging observation that the outcome of TLR signaling is dependent on the agonist and responding cell type., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Atherosclerosis is an inflammatory disease with a strong involvement of innate immunity. Toll-like receptors (TLRs) are the best-characterized pattern recognition receptors of the innate immune system. Almost all cell types in lesions, inflammatory leukocytes and resident vascular cells alike express TLRs. TLRs are able to sense modified lipids, enhance foam cell formation, induce leukocyte recruitment, and increase cytokine and matrix metalloproteinase production within atherosclerotic lesions. As such, TLRs represent an important link between atheroma and inflammation, making them attractive targets for the treatment of cardiovascular disease. Novel TLR-specific biologics are being developed and tested in other inflammatory diseases. This article will describe the exciting potential of TLRs as therapeutic targets for the treatment of atherosclerosis and will also highlight the potential challenges in the clinical application of TLR-based therapeutics in cardiovascular disease.

Inflammation drives atherosclerosis. Both immune and resident vascular cell types are involved in the development of atherosclerotic lesions. The phenotype and function of these cells are key in determining the development of lesions. Toll-like receptors are the most characterised innate immune receptors and are responsible for the recognition of exogenous conserved motifs on pathogens, and, potentially, some endogenous molecules. Both endogenous and exogenous TLR agonists may be present in atherosclerotic plaques. Engagement of toll-like receptors on immune and resident vascular cells can affect atherogenesis as signalling downstream of these receptors can elicit proinflammatory cytokine release, lipid uptake, and foam cell formation and activate cells of the adaptive immune system. In this paper, we will describe the expression of TLRs on immune and resident vascular cells, highlight the TLR ligands that may act through TLRs on these cells, and discuss the consequences of TLR activation in atherosclerosis.

Macrophages are integral to the pathogenesis of atherosclerosis, but the contribution of distinct macrophage subsets to disease remains poorly defined. Using single cell technologies and conditional ablation via a LysMCre+Clec4a2flox/DTR mouse strain, we demonstrate that the expression of the C-type lectin receptor CLEC4A2 is a distinguishing feature of vascular resident macrophages endowed with athero-protective properties. Through genetic deletion and competitive bone marrow chimera experiments, we identify CLEC4A2 as an intrinsic regulator of macrophage tissue adaptation by promoting a bias in monocyte-to-macrophage in situ differentiation towards colony stimulating factor 1 (CSF1) in vascular health and disease. During atherogenesis, CLEC4A2 deficiency results in loss of resident vascular macrophages and their homeostatic properties causing dysfunctional cholesterol metabolism and enhanced toll-like receptor triggering, exacerbating disease. Our study demonstrates that CLEC4A2 licenses monocytes to join the vascular resident macrophage pool, and that CLEC4A2-mediated macrophage homeostasis is critical to combat cardiovascular disease. The contribution of distinct subsets of macrophages to atherosclerosis is poorly understood. Here the authors describe a protective subset of vascular macrophages expressing the C-type lectin receptor CLEC4A2, which licenses monocytes to join the resident vascular macrophage pool and ensures vascular homeostasis. [ABSTRACT FROM AUTHOR]