Growth Factors as Immunotherapeutic Targets in Cardiovascular Disease

Abstract

Growth factors, such as CSFs (colony-stimulating factors), EGFs (epidermal growth factors), and FGFs (fibroblast growth factors), are signaling proteins that control a wide range of cellular functions. Although growth factor networks are critical for intercellular communication and tissue homeostasis, their abnormal production or regulation occurs in various pathologies. Clinical strategies that target growth factors or their receptors are used to treat a variety of conditions but have yet to be adopted for cardiovascular disease. In this review, we focus on M-CSF (macrophage-CSF), GM-CSF (granulocyte-M-CSF), IL (interleukin)-3, EGFR (epidermal growth factor receptor), and FGF21 (fibroblast growth factor 21). We first discuss the efficacy of targeting these growth factors in other disease contexts (ie, inflammatory/autoimmune diseases, cancer, or metabolic disorders) and then consider arguments for or against targeting them to treat cardiovascular disease. Visual Overview- An online visual overview is available for this article.

Keywords: atherosclerosis; immunotherapy; inflammation; myeloid cells.

Figure 1.

Pathologic effects of colony-stimulating factors in cardiovascular disease. M-CSF, GM-CSF, and IL-3 promote hematopoiesis in the bone marrow and spleen by triggering hematopoietic stem and progenitor cell proliferation, survival, and differentiation into myeloid cell subsets (i.e. monocytes and neutrophils), especially in the setting of hypercholesterolemia. Myeloid cells are recruited from the blood into cardiovascular organs, including the arterial vessels and myocardial tissues, via chemokine gradients established in part by CSFs acting on cells in the tissue sites (e.g. cardiac macrophages). In the intima of arterial vessels, GM-CSF and M-CSF promote the differentiation of monocytes into macrophages and monocyte-derived DCs, macrophage proliferation, activation, and production of inflammatory mediators and chemokines, foam cell formation via scavenger receptor upregulation, and cell death in advanced lesions, all of which contribute to inflammation and the accrual of leukocytes. Although GM-CSF also promotes the accumulation of CD11c⁺ dendritic cells and T cells in plaques, it is unclear whether this occurs directly or indirectly. Within cardiac tissues in settings of myocardial inflammation (e.g. MI, KD, myocarditis), GM-CSF produced by fibroblasts can stimulate myeloid cell recruitment by signaling on cardiac macrophages’ production of chemoattractants as well as stimulate bone marrow hematopoiesis distally via the circulation. M-CSF secreted by cardiac macrophages can also promote distal bone marrow myelopoiesis in myocarditis. CD4⁺ T cells promote cardiac fibroblasts’ production of GM-CSF in part via the production of IL-17A. In myocarditis, IL-3 produced by autoreactive T cells stimulates cardiac macrophages to produce monocyte chemoattractants, which guides monocyte recruitment and differentiation into monocyte-derived APCs. In turn, monocyte-derived APCs stimulate local T cell proliferation which thereby fuels leukocyte accumulation and cardiac inflammation.

Figure 2.

Pathologic effects of epidermal growth factor receptor in cardiovascular disease. Most work surrounding the pathologic effects of EGFR on vascular inflammation has focused on smooth muscle cell proliferation, migration, and survival, and endothelial cell activation and dysfunction, though more recent data has suggested EGFR also affects cardiomyocytes and fibroblasts. Regarding the immune effects of EGFR in CVD: (a) EGFR promotes macrophage accumulation, activation, foam cell formation, and macrophage production of inflammatory mediators in atherosclerotic vessels. Though EGF has been reported to mediate monocyte adhesion and chemotaxis as well as macrophage proliferation in vitro, it remains unknown whether EGF:EGFR interactions (including which EGFs) drive monocyte recruitment, differentiation, and macrophage proliferation in vivo. (b, c) EGFR promotes CD4⁺ T cell proliferation and cytokine production as well as T cell accumulation in peripheral lymphoid organs and atherosclerotic plaques. It is unknown whether EGFR signaling affects CD4⁺ T helper cell differentiation in atherosclerosis, drives T cell recruitment into atherosclerotic plaques, or affects local T cell proliferation and cytokine production in plaques.

Figure 3.

Protective effects of fibroblast growth factor 21 in cardiovascular disease. Most work on the protective effects of FGF21 in CVD has focused on FGF21 signaling primarily in tissues, such as the liver, kidney, adipose tissue, and heart (i.e. effects on cardiomyocytes). The induction of angiotensin converting enzyme 2 (ACE2) in adipocytes and renal cells by FGF21 attenuates pathologic vascular remodeling, fibrosis, and inflammation in hypertension. The induction of adiponectin in adipocytes and the liver by FGF21 limits vascular inflammation in atherosclerosis and cardiac dysfunction in MI and suppresses smooth muscle cell proliferation and macrophage oxLDL uptake directly. In atherosclerosis, FGF21 directly inhibits cholesterol biosynthesis by signaling on hepatocytes. The immune effects of FGF21 have primarily been studied in vitro (see box). FGF21 suppresses macrophage pro-inflammatory cytokine production and foam cell formation by inducing the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and upregulation of cholesterol efflux machinery (e.g. ABCA1, ABCG1) in vitro. It is unknown whether FGF21 impacts myeloid cell and other leukocyte functions in cardiovascular disease in vivo.