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Activator-Mediated Pyruvate Kinase M2 Activation Contributes to Endotoxin Tolerance by Promoting Mitochondrial
Zhujun Yi1, Yilin Wu1, Wenfeng Zhang1
1Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Abstract:
Pyruvate kinase M2 (PKM2) is a key glycolysis enzyme, and its effect on macrophages has not been entirely elucidated. Here, we identified that the PKM2 small-molecule agonist TEPP-46 mediated PKM2 activation by inducing the formation of PKM2 tetramer and promoted macrophage endotoxin tolerance. Lipopolysaccharide (LPS)-tolerant mice had higher expression of the PKM2 tetramer, which was associated with a reduced in vivo immune response to LPS. Pretreatment of macrophages with TEPP-46 resulted in tolerance to LPS stimulation, as demonstrated by a significant reduction in the production of TNF-α and IL-6. We found that TEPP-46 induced mitochondrial biogenesis in macrophages. Inhibition of mitochondrial biogenesis by mtTFA knockdown effectively inhibited TEPP-46-mediated macrophage tolerance to endotoxins. We discovered that TEPP-46 promoted the expression of PGC-1α and that PGC-1α was the key regulator of mitochondrial biogenesis in macrophages induced by TEPP-46. PGC-1α was negatively regulated by the PI3K/Akt signaling pathway. Knockdown of PKM2 or PGC-1α uniformly inhibited TEPP-46-mediated endotoxin tolerance by inhibiting mitochondrial biogenesis. In addition, TEPP-46 protected mice from lethal endotoxemia and sepsis. Collectively, these findings reveal novel mechanisms for the metabolic control of inflammation and for the induction of endotoxin tolerance by promoting mitochondrial biogenesis. Targeting PKM2 appears to be a new therapeutic option for the treatment of sepsis and other inflammatory diseases.
Insights
TEPP-46 activates pyruvate kinase M2 (PKM2) to induce macrophage endotoxin tolerance via mitochondrial biogenesis. This metabolic reprogramming offers a potential therapeutic strategy for sepsis and inflammatory diseases.
Area of Science:
- Immunology
- Metabolic pathways
- Cellular biology
Background:
- Pyruvate kinase M2 (PKM2) is a key glycolytic enzyme with incompletely understood roles in macrophages.
- Macrophage activation and inflammatory responses are critical in sepsis and endotoxemia.
Purpose of the Study:
- To elucidate the role of PKM2 in macrophage endotoxin tolerance.
- To investigate the underlying mechanisms of PKM2-mediated immune modulation.
Main Methods:
- PKM2 activation using TEPP-46 in macrophages and mice.
- Assessment of inflammatory markers (TNF-α, IL-6) and immune response.
- Analysis of mitochondrial biogenesis and key regulatory pathways (PGC-1α, PI3K/Akt).
- Gene knockdown studies (mtTFA, PKM2, PGC-1α).
Main Results:
- TEPP-46 activated PKM2, induced tetramer formation, and promoted macrophage endotoxin tolerance.
- TEPP-46-induced tolerance was linked to increased mitochondrial biogenesis, regulated by PGC-1α.
- Inhibition of mitochondrial biogenesis or PGC-1α abolished TEPP-46-mediated tolerance.
- TEPP-46 administration protected mice from lethal endotoxemia and sepsis.
Conclusions:
- PKM2 activation by TEPP-46 induces endotoxin tolerance through PGC-1α-mediated mitochondrial biogenesis.
- This study reveals a novel metabolic pathway for controlling inflammation.
- Targeting PKM2 presents a promising therapeutic avenue for sepsis and inflammatory conditions.
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