CD40 in coronary artery disease: a matter of macrophages?

Abstract

Coronary artery disease (CAD), also known as ischemic heart disease (IHD), is the leading cause of mortality in the western world, with developing countries showing a similar trend. With the increased understanding of the role of the immune system and inflammation in coronary artery disease, it was shown that macrophages play a major role in this disease. Costimulatory molecules are important regulators of inflammation, and especially, the CD40L-CD40 axis is of importance in the pathogenesis of cardiovascular disease. Although it was shown that CD40 can mediate macrophage function, its exact role in macrophage biology has not gained much attention in cardiovascular disease. Therefore, the goal of this review is to give an overview on the role of macrophage-specific CD40 in cardiovascular disease, with a focus on coronary artery disease. We will discuss the function of CD40 on the macrophage and its (proposed) role in the reduction of atherosclerosis, the reduction of neointima formation, and the stimulation of arteriogenesis.

Keywords: Arteriogenesis; Atherosclerosis; CD40; Ischemic heart disease; Macrophage; Neointima formation.

Fig. 1

Overview of the main pathways involved in CD40-TRAF signaling. a TRAF 2/3/5 induces about 40 % of TNF production; however, they do not influence (canonical) NF-κB. Therefore, an alternative pathway must be present. Based on data from B-cells, this is most likely the non-canonical NF-κB pathway. b TRAF 2/3/5 is required for the IKK-complex; however, they do not influence (canonical) NF-κB. Therefore, an alternative pathway is likely present. c Much of the downstream targets of CD40-TRAF signaling still need to be uncovered. Of the majority of molecules produces by macrophages in response to CD40 signaling, no TRAF molecule or further pathway has been determined

Fig. 2

Overview of the proposed mechanisms of CD40 (-TRAF6) inhibition on ischemic heart diseases. a In neointima formation, CD40(-TRAF6) inhibition reduces monocyte/macrophage recruitment into the vessel wall and shifts the macrophage subset balance toward the regulatory M2 phenotype. CD40(-TRAF6) inhibition markedly reduces neointima formation. b In atherosclerosis, CD40(-TRAF6) inhibition induces Ly6C low monocytosis in mice (the human counterpart to Ly6C low is CD14+/CD16++). Furthermore, it reduces monocyte/macrophage recruitment into the plaque, shifts the macrophage subset balance toward the regulatory M2 phenotype and reduces the formation of foam cells. CD40(-TRAF6) inhibition abolishes atherosclerosis. c In arteriogenesis, CD40(-TRAF6) inhibition induces Ly6C low monocytosis in mice (the human counterpart to Ly6C low is CD14+/CD16++). Moreover, shifts the macrophage subset balance toward the regulatory M2 phenotype. Both these changes have been shown to be highly beneficial in arteriogenesis