Innate immunity and monocyte-macrophage activation in atherosclerosis

Abstract

Innate inflammation is a hallmark of both experimental and human atherosclerosis. The predominant innate immune cell in the atherosclerotic plaque is the monocyte-macrophage. The behaviour of this cell type within the plaque is heterogeneous and depends on the recruitment of diverse monocyte subsets. Furthermore, the plaque microenvironment offers polarisation and activation signals which impact on phenotype. Microenvironmental signals are sensed through pattern recognition receptors, including toll-like and NOD-like receptors - the latter of which are components of the inflammasome - thus dictating macrophage behaviour and outcome in atherosclerosis. Recently cholesterol crystals and modified lipoproteins have been recognised as able to directly engage these pattern recognition receptors. The convergent role of such pathways in terms of macrophage activation is discussed in this review.

Figure 1

Macrophages have classically been described as M1 and M2. These two phenotypes differ substantially with respect to the expression of macrophage associated genes. More recently, Kadl et al have described a new subset termed MOX macrophages [36]. These are induced by an environment rich in structurally defined oxidation products such as oxidised 1-palmitoyl-2-arachidonoyl-sn-3-phosphorylcholine (oxPAPC) and can be induced from an M1 or M2 phenotype. ARE, antioxidant responsive elements; ARG1, arginase 1; CCL, chemokine ligand; COX2, cyclo-oxygenase 2; CXCL, chemokine CXC motif ligand; FIZZ1, found in inflammatory zone 1; GR, galactose receptor; HO1, heme-oxygenase 1; IL, interleukin; IL1ra; interleukin 1 receptor antagonist; ILR2, interleukin 1 receptor type II, decoy receptor; iNOS, inducible nitric oxide synthase; NRF2, nuclear factor erythroid 2-like 2; SR, scavenger receptor; Ym1, chitinase 3-like 3 lectin.

Figure 2

The interaction between innate signalling, through TLRs, and inflammasome signalling in the transcription and translation of the pro-inflammatory cytokine IL1. Oxidised LDL is a ligand for TLR, resulting in IL1 RNA transcription. Inflammasomes (which may be activated by cholesterol crystals [21]) initiate intracellular pathways which result in the post-translational modification and, ultimately the secretion of IL1 protein. Therefore, a connection between TLR and inflammasome pathways in the innate inflammatory process in atherosclerosis is alluded to. ASC, apoptosis-associated speck-like protein containing a CARD; CARD, caspase recruitment domain; CD, cluster of differentiation; ECM, extra-cellular matrix; IκB, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor; IL, interleukin; IRAK, interleukin 1 receptor-associated kinase; LPS, lipopolysaccharide; MAL, MyD88 adaptor-like; MyD88, myeloid differentiation primary response gene 88; NALP3, nucleotide-binding oligomerization domain-like receptor P3; NFκB, nuclear factor kappa B; PAMPs, pathogen-associated molecular patterns; TLR, toll-like receptor, TRAF, tumour necrosis factor receptor associated factor.

Figure 3

Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor with potent anti-inflammatory properties that modulates the immune inflammatory response. It has been observed in human atherosclerotic lesions and is involved in macrophage cholesterol homeostasis, cellular differentiation, lipid storage, insulin modulation, macrophage lipid homeostasis and anti-inflammatory activities. Molecules such as oxidised low density lipoprotein (oxLDL) or fatty acids may stimulate inflammatory mediators such as 9- and 13- hydroxyoctadecadienoic acid (HODE) generated via the 12,15 lipoxygenase pathway. These are ligands for PPARγ. IL4 is a cytokine that can stimulate PPARγ. PPARγ activation is also associated with the expression of M2 macrophage markers such as the mannose receptor (MR) also known as CD206 [40]. AMAC1, alternative activated macrophage associated CC-chemokine 1; AP1, activator protein 1; CD, cluster of differentiation; IL, interleukin; NFκB, nuclear factor kappa B; SR, scavenger receptor; STAT, signal transducer and activator of transcription.