Serglycin regulates macrophage differentiation and is associated with human atherosclerotic plaque stability

Inflammation contributes to the destabilization of atherosclerotic plaques and increases the risk of cardiovascular events such as myocardial infarction and stroke. Extracellular matrix components modulate inflammation and immune responses within the plaque microenvironment. Serglycin (SRGN), is a proteoglycan primarily expressed by immune cells that regulates inflammation, but its role in human atherosclerotic plaques remains unclear. SRGN protein levels were quantified by ELISA in carotid endarterectomy samples from patients in the Atherosclerotic Plaque Imaging Project and compared between symptomatic and asymptomatic plaques. SRGN spatial localization was evaluated by multispectral imaging and histology. Glycosylation patterns were examined by immunoprecipitation and immunoblotting. Functional effects were investigated using CRISPR-mediated SRGN knockout in THP-1 monocytes differentiated into macrophages and exposed to oxidized low-density lipoprotein (oxLDL). SRGN levels were higher in plaques from asymptomatic patients compared with plaques from symptomatic patients and localized primarily to macrophage- and lipid-rich regions. Plaque SRGN was positively associated with histological markers of plaque stability, displayed heterogeneous molecular forms and showed an inverse association with the plaque vulnerability index. In vitro, SRGN deficiency was associated with a more pro-inflammatory macrophage profile, impaired M2-like polarization, and increased lipid retention following oxLDL exposure. These findings indicate that SRGN is associated with inflammatory cell presence, lipid accumulation, and features of plaque stability in human plaques, and suggest a role for SRGN in macrophage differentiation and lipid handling in atherosclerotic lesions.