FIGURE 5. The importance of neutrophils, endothelium and macrophages HSPGs in atherogenesis.

Vascular HSPGs such as perlecan (HSPG2) and COL18 are responsible for trapping of LDL entering the subendothelial vessel wall. Trapped LDL aggregates (agLDL) undergo oxidation by reactive oxygen species and partial lipolysis by sPLA2, thereby generating modified LDL (mLDL). The process activates the overlying endothelium to express vascular adhesion molecule-1 (VCAM1) which stimulates infiltration of monocytes. Invested monocytes will differentiate into macrophages and clear mLDL via syndecan 4 (SDC4) and other scavenger receptors (not shown). The macrophages convert into sedentary foams cells that will reside in the intima of the arteries where they perpetuate a chronic inflammatory response that will drive further infiltration of monocytes. Monocytes expressing SDC1 and sulfated HSPGs will differentiate into the resolving Ly6C^low macrophages (Ly6C^low) due to reduced Type I interferon (IFN) signaling. Monocytes lacking HS sulfation and SDC1 are more susceptible to Type I IFN and differentiate into classical proinflammatory Ly6C^high macrophages (Ly6C^high) secreting cytokines such as CCL2 and CCL5 that aggravate the chronic inflammation. Increased Type I IFN signaling will also result in increased expression of ACAT1 and ACAT2 and promote foam cell conversion of Ly6C^high macrophages. SDC4 can also modulate the infiltration of neutrophils and based on indirect observations (smaller arrows). Evidence suggests that antithrombin (AT) blocks SDC4-mediated infiltration of neutrophils if HS3ST1 is expressed by the endothelial cells. The increased neutrophil influx will further increase the secretion of Type I IFN by plasmacytoid dendritic cells (pDC). The overall process promotes a self-perpetuating cycle, resulting in excessive foam cell conversion, lipid-induced necrosis, in the formation of a necrotic core and unstable lesions that can rupture and clog arteries.