Glycolytic reprogramming in macrophages and MSCs during inflammation

Area of Science:

• Biochemistry
• Cell Biology
• Immunology

Background:

• Dysregulated inflammation is linked to skeletal diseases like osteoarthritis and non-unions.
• Contaminated polyethylene particles (cPE) induce prolonged inflammation and impair bone formation.
• Cellular bioenergetics and mitochondrial function in bone inflammation remain poorly understood.

Purpose of the Study:

• To investigate the metabolic and bioenergetic reprogramming in macrophages (Mφ) and mesenchymal stromal cells (MSCs) under inflammatory conditions induced by cPE.
• To determine if glycolytic reprogramming and mitochondrial dysfunction contribute to impaired immunoregulation and bone regeneration.

Main Methods:

• Utilized Seahorse XF96 analyzer to assess mitochondrial respiration (oxygen consumption rate) and glycolysis (extracellular acidification rate) in Mφ and MSCs exposed to cPE.
• Employed real-time qPCR to analyze gene expression of key metabolic enzymes and inflammatory markers.
• Quantified real-time ATP production rates from oxidative phosphorylation (OXPHOS) and glycolysis.

Main Results:

• Mφ exposed to cPE exhibited significantly decreased oxidative phosphorylation and increased glycolysis, with a higher reliance on glycolytic ATP (glycoATP).
• MSCs showed enhanced glycolysis but no significant change in oxygen consumption rates, with elevated glycoATP.
• Both Mφ and MSCs exposed to cPE displayed upregulated glycolytic regulators, and Mφ showed increased pro-inflammatory cytokine expression.

Conclusions:

• cPE exposure induces dysfunctional bioenergetic activity in bone marrow-derived Mφ and MSCs, potentially impairing their immunoregulatory functions within the bone niche.
• Disordered mitochondrial function and metabolic reprogramming represent a potential therapeutic target for resolving inflammation in skeletal diseases.