Immunological perspectives on atherosclerotic plaque formation and progression

Abstract

Atherosclerosis serves as the primary catalyst for numerous cardiovascular diseases. Growing evidence suggests that the immune response is involved in every stage of atherosclerotic plaque evolution. Rapid, but not specific, innate immune arms, including neutrophils, monocytes/macrophages, dendritic cells (DCs) and other innate immune cells, as well as pattern-recognition receptors and various inflammatory mediators, contribute to atherogenesis. The specific adaptive immune response, governed by T cells and B cells, antibodies, and immunomodulatory cytokines potently regulates disease activity and progression. In the inflammatory microenvironment, the heterogeneity of leukocyte subpopulations plays a very important regulatory role in plaque evolution. With advances in experimental techniques, the fine mechanisms of immune system involvement in atherosclerotic plaque evolution are becoming known. In this review, we examine the critical immune responses involved in atherosclerotic plaque evolution, in particular, looking at atherosclerosis from the perspective of evolutionary immunobiology. A comprehensive understanding of the interplay between plaque evolution and plaque immunity provides clues for strategically combating atherosclerosis.

Keywords: atherosclerosis; immune cell heterogeneity; immune response; immunotherapy; inflammatory microenvironment; plaque evolution.

Figure 1

Evolution of immune cells in the development of atherosclerotic plaques. Early in the lesion, monocytes/macrophages predominate. Monocytes differentiate into macrophages, which can uptake oxLDL to become foam cells, and also differentiate into inflammatory macrophages and IFNICs macrophages, which secrete IL-1, TNF-α, and type I interferon to exert pro-inflammatory effects, respectively; in addition, they can also be polarized into the M1, M4, and Mox phenotypes, which secrete pro-inflammatory cytokines such as IL-1β, TNF-α, IL-6, or MMP, promoting atherosclerosis. In all stages of atherosclerosis, ILC1 is identified as the most abundant subset of ILCs and is involved in reinforcing plaque formation through the production of IFN-γ. Atherosclerotic lesions trigger migration and activation of NK cells as well as release of pro-atherogenic factors IFN-γ and TNF-α. Neutrophils secrete pro-inflammatory mediators such as NETs, TNF-α, IL-1, IL-6 and IL-8, increasing plaque inflammation and susceptibility to rupture. A large number of B cells with a structure similar to tertiary lymphoid organs are found in the adventitial layer of blood vessels, in which B2 cells secrete mediators that aggravate atherosclerosis such as IgG and BAFF. In advanced atherosclerosis, numerous T cells homing to the plaque. Activated DCs present cognate peptides on MHC class I molecules to CD8⁺T cells and on MHC class II molecules to CD4⁺T cells. Activated CD8⁺T cells exert atherogenic effects by secreting perforin and granzyme B and inducing cell death. CD4⁺T cells are polarized into different subsets, and Th1 cells are able to further stimulate foam cell formation and exacerbate atherosclerosis through the secretion of their major cytokine, IFN-γ. IL-17 secreted by Th17 cells may accompany the increase of IFN-γ to promote plaque inflammatory response and play pro-atherogenic roles.

Figure 2

Heterogeneity of monocytes/macrophages and DCs in atherosclerotic lesions. Monocytes and DCs share a common origin in myeloid progenitor (MP). Monocyte-DC precursor (MDP) gives rise to monocytes and common DC precursor (CDP). Among them, mouse monocytes are classified into two subsets according to their surface expression of Ly-6C. Ly6C^hi subsets have pro-inflammatory functions and highly express CCR2. Ly6C^low subsets primarily patrol along the vascular endothelium, are engaged in tissue repair, and can express CD11c, and differentiate into inflammatory DCs to promote plaque progression in the plaque inflammatory microenvironment. Human monocytes are subdivided into three subsets based on the expression of CD14 and CD16.CD14⁺⁺CD16^- classical monocytes, which express high levels of CCR2, can differentiate into CD14⁺⁺CD16⁺ intermediate monocytes that express CCR5, and then further differentiate into CD14⁺CD16⁺⁺ nonclassical monocytes, which are highly expressive of CX3CR1. Once monocytes enter the intima, they can mature into macrophages. Differentiation of different macrophage subsets depends on the stimulation of the inflammatory microenvironment within the lesion. Pro-atherogenic macrophages include M1, M4, and Mox, which are activated by Th1 cytokines, CXCL4, and OxPL, respectively, and secrete pro-inflammatory mediators, such as TNF-α, MMP, and IL-1β, to exert pro-inflammatory effects. Anti-atherogenic macrophages include M(Hb), Mhem, and M2. M(Hb) and Mhem are induced by Hb and Heme and secrete CD163 and CD206 to exert anti-inflammatory effects. M2 macrophages are subdivided into M2a, activated by IL-4 and IL-13; M2b, activated by IC; M2c, activated by IL-10, TGF-β and GC, and M2d, activated by IL-6 and ADORA2A. M2 macrophages mainly secrete Th2 cytokines such as IL-10 as well as TGF-β, which inhibit the development in atherosclerosis. CDP can further differentiate into pDCs and pre-DCs, and pre-DCs enter the arterial intima and become pDCs and cDCs, respectively, and play pro-atherogenic roles by secreting TNF or IFN.