Homocysteine Activates B Cells via Regulating PKM2-Dependent Metabolic Reprogramming

Area of Science:

• Immunology
• Metabolic pathways
• Cardiovascular disease research

Background:

• Immune cell overactivation contributes to hyperhomocysteinemia (HHcy)-accelerated atherosclerosis.
• Homocysteine (Hcy) promotes B cell proliferation and antibody (Ab) secretion, but mechanisms are unclear.
• Metabolic reprogramming is essential for lymphocyte activation and function.

Purpose of the Study:

• To elucidate the mechanisms by which Hcy affects B cell metabolism and function.
• To investigate the role of pyruvate kinase muscle isozyme 2 (PKM2) in Hcy-induced B cell activation.
• To evaluate PKM2 inhibition as a therapeutic strategy for HHcy-accelerated atherosclerosis.

Main Methods:

• Analysis of metabolic changes (oxidative phosphorylation, glycolysis, pentose phosphate pathway) in Hcy-activated B cells.
• Assessment of PKM2 expression and activity in B cells.
• In vivo and in vitro experiments using PKM2 inhibitor shikonin and mechanistic target of rapamycin (mTOR) inhibitor rapamycin.
• Evaluation of atherosclerotic lesion formation in apolipoprotein E-deficient mice treated with shikonin.

Main Results:

• Hcy-activated B cells showed increased glycolysis and pentose phosphate pathway activity.
• Hcy elevated PKM2 expression and activity in B cells.
• Shikonin treatment reversed Hcy-induced metabolic changes, B cell proliferation, and Ab secretion.
• Rapamycin inhibited Hcy-induced PKM2 changes and B cell activation, implicating the Akt-mTOR pathway.
• Shikonin treatment reduced atherosclerotic lesion progression in HHcy mice.

Conclusions:

• PKM2 is crucial for metabolic reprogramming that supports Hcy-induced B cell activation and function.
• Targeting PKM2 may offer a novel therapeutic approach to mitigate HHcy-accelerated atherosclerosis.
• The Akt-mTOR pathway is involved in regulating PKM2 in Hcy-activated B cells.