IL-6R (trans-signaling) is a key regulator of reverse cholesterol transport in lipid-laden macrophages

Abstract Background Atherosclerosis epitomizes a multifaceted cardiovascular disorder, predominantly characterized by the accumulation of cholesterol-laden plaques within arterial walls. Despite substantial research, the precise mechanisms governing the formation of these cholesterol-rich plaques remain partially elucidated. This study delves into the complex interplay of interleukin-6 (IL-6) receptors, shedding light on their pivotal role in orchestrating cholesterol homeostasis in human macrophages. Methods This investigation evaluated the correlation between interleukin-6 (IL-6), its receptors (IL6R/CD126), and glycoprotein 130 (gp130), alongside established atherosclerosis biomarkers. The cohort comprised 142 subjects, balanced between lean and obese individuals (71 each). Subsequent analyses utilized THP-1-derived macrophages to discern the biochemical repercussions of inhibiting IL-6 receptors on cellular mechanisms. Results Data indicates a significant upsurge in IL-6 secretion correlating with atherosclerotic manifestations in the obese subset, accompanied by a concomitant diminution in IL-6 receptors IL6R/CD126 and gp130 on circulating monocytes within this group. Pharmacological obstruction of the gp130 receptor in macrophages provoked pronounced alterations in lipid metabolism, notably impacting cholesterol management. These alterations were evidenced by an escalated expression of the LDLR gene, responsible for cholesterol uptake, and a surge in de novo cholesterol synthesis, marked by the upregulation of SREBF2 and its downstream effector, mevalonate kinase (MVK). Concurrently, an increase in HMG-CoA reductase protein levels was observed. Intriguingly, a rise in intracellular cholesterol production coupled with a reduction in ABCA1 levels was noted, suggesting a potential impediment in cholesterol efflux in cells deficient in gp130. This hypothesis was further substantiated by Filipin III staining, which indicated cholesterol retention in cells subjected to gp130 inhibition. Clinical implications of these discoveries were corroborated through experiments on PBMCs from lean participants, where the gp130 inhibitor curtailed cholesterol efflux to levels comparable to those in untreated cells. Conclusion Collectively, our research underscores the instrumental role of gp130 in the reverse cholesterol transport pathway of macrophages. These insights pave the way for novel therapeutic strategies targeting atherosclerosis and its associated cardiovascular complications, spotlighting gp130 as a potential focal point for intervention.