Activator-Mediated Pyruvate Kinase M2 Activation Contributes to Endotoxin Tolerance by Promoting Mitochondrial Biogenesis

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.

Mediation of PKM2-dependent glycolytic and non-glycolytic pathways by ENO2 in head and neck cancer development

“…Consistent with the previous study [ 44 ], compound 3k treatment resulted in cytotoxicity in all HNSCC cell lines examined through inhibiting PKM2 function. Interestingly, several small molecules that selectively activate PKM2 over other pyruvate kinase isoforms, such as DASA-58 and TEPP-46, were also discovered as an anticancer therapeutic strategy by inducing tetramerization of the kinase and suppressing lactate secretion[ 47 , 48 ]. Here, we show that depletion of ENO2 induces HNSCC remission through impairing metabolic and nonmetabolic roles of PKM2, providing new evidence that targeting PKM2 in HNSCC cells could be a therapeutic option to further investigate.…”

Expression of PKM2 in wound keratinocytes is coupled to angiogenesis during skin repair in vivo and in HaCaT keratinocytes in vitro

“…However, their finding was independent of Stat3 or Stat1 activation. Similarly, metabolic activation of Pkm2 has been shown to restrain pro-inflammatory activation of murine macrophages by reducing the formation of Hif-1α-Pkm2 ternary complex at IL-1β promoter [ 66 ] or induce mitochondrial biogenesis [ 67 ]. Interestingly, activation of PKM2 tetramer formation TEPP-46 did not alter VEGF production in EGF-stimulated HaCaT cells (Fig.…”

PKM2 deficiency exacerbates gram-negative sepsis-induced cardiomyopathy via disrupting cardiac calcium homeostasis

“…After LPS stimulation for 24 h, the mice were sacrificed for subsequent experiments. The CLP surgery procedure was similar to previous studies with minor modifications [ 52 ]. Briefly, mice were anesthetized with 2% isoflurane (RWD, R510-22-4) with a maintained 37 °C body temperature.…”

“…In this study, gram-negative sepsis-induced cardiomyopathy model was established with lipopolysaccharide (LPS) (Sigma; L2280) or cecal ligation and puncture (CLP) [ 52 , 53 ]. For LPS-induced cardiomyopathy, mice weighed 22.3 ± 2.5 g were randomly underwent an intraperitoneal injection of LPS (10 mg/kg) or saline equally.…”