The CD40 protein, which is a type I transmembrane receptor, exists in trimers, and this trimerization is crucial for its activation. The extracellular region of CD40 is cysteine-rich (consisting of 20 residues). The CD40 protein consists of 4 cysteine-rich domains, and every domain is divided into 2 cysteine modules (A1, A2, B1, B2). The CD40 ligand (CD40L) protein is a type II membrane protein with an intracellular amino terminus and an external carboxy terminus. Its extracellular region belongs to the tumor necrosis factor (TNF) superfamily. The CD40L is stored in -granules in unstimulated platelets but rapidly translocates to the platelet surface when platelets are activated. The surface-expressed CD40L is then cleaved and shed from the platelet surface as soluble CD40 ligand (sCD40L). C = C-terminal; N = N-terminal.

Activated platelets express CD40 ligand (CD40L), which is then cleaved and released as soluble CD40 ligand (sCD40L). The sCD40L binds to circulating monocytes through both its receptor CD40 and through monocyte/macrophage integrin Mac-1, promoting their adhesion to vascular endothelium. The sCD40L also binds to CD40 on endothelial cell (EC) surfaces, which are then activated (by triggering the overexpression of transcriptional factors such as nuclear factor-kappa B [NF-β], activator protein [AP]-1, and others) to express adhesion molecules such as E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) on EC surfaces. These molecules mediate the adhesion and transmigration of monocytes to subendothelial space. Activated ECs and smooth muscle cells (SMCs) also produce proinflammatory molecules such as monocyte chemoattractant protein (MCP)-1 and interleukins (ILs); they release prothrombotic mediators such as tissue factor; and they overexpress enzymes generating reactive oxygen species (ROS). The ROS oxidize low-density lipoprotein (LDL) to oxidized low-density lipoprotein (Ox-LDL) which is up-taken by activated macrophages, which are turned into foam cells. CD40L also activates SMCs and fibroblasts, which are proliferated and migrate to further induce atherogenesis. Red rectangles = E-selectin; red receptors = Mac-1; yellow triangles = VCAM; and blue triangles = ICAM. MMP = matrix metalloproteinase; NO = nitric oxide; VSMC = vascular smooth muscle cells.