Endoplasmic Reticulum Stress Promotes the Expression of TNF-α in THP-1 Cells by Mechanisms Involving ROS/CHOP/HIF-1α...

Area of Science:

• Cellular Biology
• Immunology
• Metabolic Disorders

Background:

• Obesity and metabolic syndrome are linked to metabolic inflammation, characterized by chronic low-grade inflammation, endotoxemia, and elevated free fatty acids.
• The role of endoplasmic reticulum (ER) stress in monocytic cells in amplifying metabolic inflammation and its underlying mechanisms remain debated.

Purpose of the Study:

• To investigate the cooperative interaction between metabolic stress and ER stress in monocytic cells.
• To elucidate the molecular mechanisms by which this interaction amplifies inflammation, specifically focusing on tumor necrosis factor-alpha (TNF-α) production.
• To evaluate the therapeutic potential of antioxidants in mitigating stress-induced inflammation.

Main Methods:

• Metabolic stress was induced in THP-1 cells and primary human monocytes using lipopolysaccharide (LPS), palmitic acid (PA), or oleic acid (OA), with or without thapsigargin (TG) to induce ER stress.
• Key molecular markers including TNF-α, ER/oxidative stress markers, reactive oxygen species (ROS), hypoxia-inducible factor 1-alpha (HIF-1α), and MAPK/NF-κB signaling pathways were assessed.
• Clinical relevance was examined by measuring adipose and plasma TNF-α, hs-CRP, MDA, and OX-LDL in individuals with obesity.

Main Results:

• The combined metabolic and ER stress significantly promoted the expression of TNF-α, ROS, CHOP, ATF6, SOD2, and NRF2, without impairing glucose uptake.
• TNF-α amplification was critically dependent on HIF-1α stabilization and p38 MAPK/p65 NF-κB phosphorylation.
• Inhibition of MAPK/NF-κB pathways and the use of antioxidants/ROS scavengers (curcumin, allopurinol, apocynin) effectively attenuated TNF-α production.
• Individuals with obesity exhibited increased adipose TNF-α and elevated plasma levels of TNF-α, CRP, MDA, and OX-LDL.

Conclusions:

• A cooperative model between metabolic and ER stress favors inflammation by triggering TNF-α production through ROS/CHOP/HIF-1α and MAPK/NF-κB dependent pathways.
• This interplay highlights a significant mechanism contributing to metabolic inflammation in obesity.
• Antioxidants demonstrate therapeutic promise for managing inflammatory conditions associated with metabolic and ER stresses.