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.
Highlights
The systemic inflammatory response and multiple organ failure caused by severe sepsis and septic shock are important causes of high mortality in clinical patients [1, 2]
We observed a significant increase in mitochondrial DNA copy number in RAW264.7 cells stimulated with TEPP-46 (50 ng/ml) for 0–24 h, and these results were consistent with the increased protein level of mitochondrial transcription factor A, a key regulator of mitochondrial biogenesis bound to mtDNA (Figures 2D, E)
We demonstrated that Pyruvate kinase M2 (PKM2) activation by TEPP-46 contributes to endotoxin tolerance and that PKM2 activation induces mitochondrial biogenesis in macrophages, we do not know whether PKM2 activation promotes endotoxin tolerance by inducing mitochondrial biogenesis. mitochondrial transcription factor A (mtTFA) is a key regulator of mitochondrial biogenesis bound to mtDNA [42]
Summary
The systemic inflammatory response and multiple organ failure caused by severe sepsis and septic shock are important causes of high mortality in clinical patients [1, 2]. The release of these proinflammatory cytokines induces inflammation and modulates the immune response [5]. Endotoxin tolerance provides a protective mechanism to reduce the proinflammatory cytokine levels in response to severe infection [8, 9]. Endotoxin tolerance is a double-edged sword in regulating the immune response [10]. A prolonged endotoxin-tolerant state allows for the development of secondary infections, increasing mortality from sepsis [11,12,13]. Understanding the mechanisms controlling endotoxin tolerance is important to design a good time frame for interventions to regulate the immune responses
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
