Cholesterol Byproducts Trigger Immune Cell Death, Pointing to New Heart Disease Link
Researchers found that oxysterols—toxic cholesterol variants that accumulate in arterial plaques—cause immune cells to self-destruct by suppressing a key protective protein. The discovery reveals a previously unknown mechanism linking cholesterol metabolism to inflammation and could reshape how companies develop atherosclerosis treatments and diagnostics.
Originaltitel: Reduced Membrane CD163 Expression in 7-Oxysterol-Induced Apoptosis Accompanied by Elevated Oxidative Stress.
CD163-receptorn på makrofagers yta minskar när 7-oxysterolar triggrar celldöd — en upptäckt som kan förklara varför vissa makrofager blir skörare i aterosklerosbetad. Forskare vid Linköpings universitet exponerade THP-1-makrofager för en blandning av 7β-hydroxikolesterol och 7-ketokholesterol (2mix), två oxysterolar som ansamlas i ateromatösa lesioner. Resultatet visar dosberoendet: ju högre 2mix-exponering, desto lägre CD163-nivå på cellöverflöden. Samtidigt steg reaktiv syresspecies (ROS) och apoptosmarkörerna markant. CD163-uttrycket korrelerade omvänt med både celldöd och oxidativ stress. Studien föreslår att CD163 skyddar makrofager mot oxysterol-inducerad apoptosis. För läkemedelsföretag som utvecklar atheroskleros-terapier betyder detta att CD163-modulering kan påverka plackstabilitet. Resultat från Linköpings kliniska avdelning för obstetrik och gynekologi och institutionen för biomedicinsk och klinisk vetenskap öppnar nya målstrukturer för inflammationshämmande strategier.
CD163 is a transmembrane scavenger receptor predominantly expressed by activated M2-like macrophages and is involved in inflammatory processes. Oxysterols, which accumulate in atherosclerotic lesions, are known to induce oxidative stress and apoptosis in macrophages. However, the relationship between CD163 expression and apoptosis induced by oxysterols remains poorly understood. Our brief report presents an examination of the effects of an atheroma-relevant mixture of 7β-hydroxycholesterol and 7-ketocholesterol (2mix) on cell surface CD163. THP-1 monocytes/macrophages were exposed to 2mix, and the surface expressions of CD163, apoptosis, and reactive oxygen species (ROS) production were assessed using flow cytometry and fluorescence microscopy. Exposure to 7-oxysterols induced a dose-dependent reduction in cell surface CD163 expression, with significant decreases observed in R1 and R2 cell populations but not in R3. This decrease was accompanied by a significant increase in apoptosis and ROS production. Notably, CD163 expression was inversely correlated with both apoptotic cell death and oxidative stress levels. Our findings suggest that macrophage surface CD163 may exert a protective role against 7-oxysterol-induced apoptosis and oxidative stress. This indicates a potential function of CD163 in macrophage survival and highlights its possible importance for plaque stability in atherosclerotic lesions.