Innate immunity in atherosclerosis : the role of pattern recognition receptors

The pathogenesis of atherosclerosis is greatly influenced by the activities of both innate and adaptive immunity. Danger signals such as cholesterol crystals, oxidized LDL, and modified phospholipids may trigger sterile inflammation in atherosclerosis. Systemic infection or transient release of pathogen associated molecules in the circulation might also activate immune system and affect atherosclerosis. Activation of the innate immunity relies on a set of pattern recognition receptors (PRRs). Thus, PRRs are fundamental for activating the innate immunity in atherosclerosis.

This thesis focuses on the role of three different PRRs in atherosclerosis, including NOD1, NOD2 and TLR9. We hypothesized that these PRRs regulate immune responses in the pathogenesis of atherosclerosis. We found that NOD2 is expressed in endothelial cells and macrophages in atherosclerotic plaques, and lesional NOD2 signal leads to activation of PGE2 pathway via NF-kB and MAPK p38. NOD2 activation in vivo promotes the development of vulnerable atherosclerotic plaques, characterized by enlarged necrotic core in the atherosclerotic plaques and enhanced vascular inflammation. Furthermore, NOD2 induces lipid retention in macrophages may contribute to the necrotic core formation. Although belonging to the same family, NOD1 signal promotes another lesional phenotype characterized by occlusive atherosclerosis with elastin degradation and vascular smooth muscle cell (VSMC) activation. In vitro stimulation of SMCs with NOD1 ligand induces chemokine and MMP production as well as enhances migration ability. Our data point to a possible mechanism via NOD1 in the development of occlusive atherosclerotic lesions. Unlike NOD1 and NOD2, TLR9 stimulation decreases atherosclerosis and necrotic core albeit activates local and systemic inflammation. Two important anti-inflammatory mediators IL-10 and IDO are induced by TLR9 activation and are potential contributors to the mechanisms that TLR9 restrains atherosclerosis.

In summary, we identified three innate immune pathways linked to the distinct features of atherosclerosis. NOD2 leads to formation of vulnerable plaques with big necrotic cores. NOD1 promotes severe occlusive atherosclerosis. TLR9 signal restrains the development of atherosclerosis.

List of scientific papers

I. Liu HQ, Zhang XY, Edfeldt K, Nijhuis MO, Idborg H, Bäck M, et al. NOD2-mediated innate immune signaling regulates the eicosanoids in atherosclerosis. Arterioscler Thromb Vasc Biol. 2013;33:2193-2201.
https://doi.org/10.1161/ATVBAHA.113.301715

II. Johansson ME, Zhang X-Y, Edfeldt K, Lundberg AM, Levin MC, Borén J, et al. Innate immune receptor NOD2 promotes vascular inflammation and formation of lipid-rich necrotic cores in hypercholesterolemic mice. Eur J Immunol. 2014 Jul 17.
https://doi.org/10.1002/eji.201444755

III. Zhang X-Y, Johansson ME, Jiang X-T, Hansson G, Yan Z-Q. Innate immune receptor NOD1 provides a mechanistic link to inflammatory destruction of arterial wall and development of severe atherosclerosis. [Manuscript]

IV. Zhang X-Y, Qiao Z-G, Berg M, Ketelhuth D, Yan Z-Q. CpG induces potent immune regulatory mechanisms that inhibit progression of atherosclerosis in hyperlipidemic mice. [Manuscript]