PGC1α enhances macrophage efferocytosis in ox-LDL-stimulated RAW264.7 cells by regulating the NLRP3/PPARα axis.

BACKGROUND

Defective clearance of apoptotic and foam cells achieved by arterial macrophage efferocytosis propels the progression of inflammatory atherosclerosis, but related molecular mechanisms in this process remain unclear. Herein, this study is engineered to probe into the mechanism of peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC1α) on atherosclerosis.

METHODS

The PGC1α/NLR family pyrin domain containing 3 (NLRP3)/peroxisome proliferator activated receptor alpha (PPARα) axis in oxidized low-density lipoprotein (ox-LDL)-induced RAW264.7 cells was verified using Western blot. Inflammatory response, NLRP3 activation, efferocytotic efficiency and lipid uptake of the ox-LDL-stimulated cells overexpressing PGC1α or/and silencing PPARα were detected by enzyme-linked immunosorbent assay, immunofluorescence, tracing of apoptotic Jurkat cells and Oil red O staining.

RESULTS

PGC1α and PPARα levels were decreased, but NLRP3 level was increased in ox-LDL-stimulated RAW264.7 cells (P<0.001). PGC1α overexpression repressed the levels of IL-1β, IL-6 and TNF-α, NLRP3 expression or activation and foam cell formation (P<0.05), but enhanced efferocytosis as well as expressions of AXL, MERTK and TYRO3 in ox-LDL-stimulated cells (P<0.001). PGC1α overexpression increased PPARα expression. However, PPARα silencing reversed the effects of PGC1α overexpression on protecting macrophages against ox-LDL-induced inflammation, efferocytotic impairment and foam cell formation (P<0.05).

CONCLUSION

Overexpression PGC1α decreased NLRP3 activation to promoted the expression of PPARα, which alleviated the impairment of macrophage efferocytosis and inhibited the development of atherosclerosis development.