Innate and adaptive immunity in cardiovascular calcification

Abstract

Despite the focus placed on cardiovascular research, the prevalence of vascular and valvular calcification is increasing and remains a leading contributor of cardiovascular morbidity and mortality. Accumulating studies provide evidence that cardiovascular calcification is an inflammatory disease in which innate immune signaling becomes sustained and/or excessive, shaping a deleterious adaptive response. The triggering immune factors and subsequent inflammatory events surrounding cardiovascular calcification remain poorly understood, despite sustained significant research interest and support in the field. Most studies on cardiovascular calcification focus on innate cells, particularly macrophages' ability to release pro-osteogenic cytokines and calcification-prone extracellular vesicles and apoptotic bodies. Even though substantial evidence demonstrates that macrophages are key components in triggering cardiovascular calcification, the crosstalk between innate and adaptive immune cell components has not been adequately addressed. The only therapeutic options currently used are invasive procedures by surgery or transcatheter intervention. However, no approved drug has shown prophylactic or therapeutic effectiveness. Conventional diagnostic imaging is currently the best method for detecting, measuring, and assisting in the treatment of calcification. However, these common imaging modalities are unable to detect early subclinical stages of disease at the level of microcalcifications; therefore, the vast majority of patients are diagnosed when macrocalcifications are already established. In this review, we unravel the current knowledge of how innate and adaptive immunity regulate cardiovascular calcification; and put forward differences and similarities between vascular and valvular disease. Additionally, we highlight potential immunomodulatory drugs with the potential to target calcification and propose avenues in need of further translational inquiry.

Keywords: Adaptive immunity; Aortic valve calcification; Atherosclerosis; B cells; Immune response; Innate immunity; Macrophages; T cells; Vascular calcification.

Figure 1:. Innate immune system in cardiovascular calcification development.

Innate immune system promotes vascular and valvular calcification through stimulation of extracellular matrix (ECM) remodeling, as well as apoptosis and osteogenic differentiation of arterial vascular smooth muscle cells (VSMCs) and valvular interstitial cells (VICs). Macrophage M1 (pro-inflammatory) and M2 (anti-inflammatory) express soluble factors that might promote calcification by inducing osteogenic differentiation and matrix metalloproteinases (MMPs) able to induce ECM remodeling. Mast cell (MC) derived enzymes degrade ECM and could be associated with induction of VSMC apoptosis. Neutrophils release NETs, leading to VSMC apoptosis, as well as platelet activation and secretion of soluble factors, which in turn may promote calcification by inducing osteogenic differentiation. ECM, Extracellular Matrix; VSMC, Vascular Smooth Muscle Cell; VIC, Valvular Interstitial Cell; ABs, Apoptotic Bodies; EVs, Extracellular Vesicles; M1, Macrophage 1; M2, Macrophage 2; MC, Mast Cell; N, Neutrophil; IL, interleukin; TNF-α, Tumor Necrosis Factor alpha; MMPs, Matrix Metalloproteinases; TGF-β, Transforming Growth Factor beta; NETs, Neutrophil Extracellular Traps; IFN-γ, Interferon gamma;

Figure 2:. Adaptive immune system in cardiovascular calcification development.

Implication of the adaptive immune system in vascular and valvular calcification is not well established. However, Interleukin-4 (IL4) secreted by T-helpers 2 (Th2) promotes osteogenic differentiation of vascular smooth muscle cells (VSMCs). T regulatory cells (Treg) release Transforming Growth Factor-β (TGF-β) capable to induce VSMCs and valvular interstitial cells (VICs) mineralization. Other cytokines described here, produced by T cell subtypes, such as cytotoxic T cell (CTL), Th1, Natural killer T cells (NKT), as well as B cells, have been correlated with calcification without direct evidence. Similar indirect evidence, based on correlation, has been observed between antibodies and calcification, suggesting influence by B cells. ECM, Extracellular Matrix; VSMC, Vascular Smooth Muscle Cell; VIC, Valvular Interstitial Cell; ABs, Apoptotic Bodies; EVs, Extracellular Vesicles; NKT, Natural Killer T cell; CTL, Cytotoxic T lymphocyte; Th, T helper; Treg, T regulatory cell; P, Plasmocyte; IL, interleukin; TGF-β, Transforming Growth Factor beta; IFN-γ, Interferon gamma; GzmB, Granzyme B; Prf, Perforin.