Regulating mitochondrial homeostasis and inhibiting inflammatory responses through Celastrol

Area of Science:

• Cardiovascular Science
• Immunology
• Cell Biology

Background:

• Coronary heart disease (CHD) presents a significant global health challenge due to high morbidity and mortality.
• Atherosclerosis, characterized by chronic blood vessel wall inflammation, is a primary pathological process underlying CHD.
• Macrophage-driven inflammation is a critical factor in the initiation and progression of atherosclerosis.

Purpose of the Study:

• To investigate the anti-inflammatory effects of Celastrol on macrophages.
• To elucidate the mechanisms by which Celastrol modulates macrophage inflammation, focusing on mitochondrial dynamics and signaling pathways.
• To explore the potential of Celastrol as a therapeutic agent for atherosclerosis.

Main Methods:

• Macrophage inflammation was induced using lipopolysaccharide (LPS).
• Cells were treated with varying concentrations of Celastrol and analyzed at different time points.
• Key molecular targets, including Nur77, inflammatory cytokines, chemokines, mitochondrial fission/fusion proteins (p-Drp1, Mfn2), and signaling pathways (NF-κB, ERK1/2, p38), were assessed using qPCR, Western Blot, and ELISA.

Main Results:

• Celastrol significantly inhibited LPS-induced inflammatory responses, down-regulating cytokines (iNOS, COX2, TNF-α) and chemokines (CCL-2, CXCL-10).
• Celastrol modulated mitochondrial dynamics by promoting Drp1 phosphorylation (Ser637), inhibiting fission, and up-regulating Mfn2, thereby promoting fusion.
• Celastrol's anti-inflammatory effects were associated with the modulation of NF-κB, ERK1/2, and p38 signaling pathways and an increase in Nur77 expression.

Conclusions:

• Celastrol exhibits anti-inflammatory properties by regulating Drp1-dependent mitochondrial fission/fusion and key signaling pathways (ERK1/2, p38, NF-κB).
• Celastrol's ability to up-regulate Nur77 expression warrants further investigation.
• These findings highlight Celastrol as a promising candidate for developing novel anti-atherosclerotic and anti-inflammatory therapies.