Pyruvate Kinase M2 Regulates Hif-1α Activity and IL-1β Induction and Is a Critical Determinant of the Warburg Effect in LPS-Activated Macrophages

Abstract

SUMMARY Macrophages activated by the TLR4 agonist LPS undergo dramatic changes in their metabolic activity. We here show that LPS induces expression of the key metabolic regulator Pyruvate Kinase M2 (PKM2). Activation of PKM2 using two well-characterized small molecules, DASA-58 and TEPP-46, inhibited LPS-induced Hif-1α and IL-1β, as well as the expression of a range of other Hif-1α-dependent genes. Activation of PKM2 attenuated an LPS-induced pro-inflammatory M1 macrophage phenotype while promoting traits typical of an M2 macrophage. We show that LPS-induced PKM2 enters into a complex with Hif-1α, which can directly bind to the IL-1β promoter, an event that is inhibited by activation of PKM2. Both compounds inhibited LPS- induced glycolytic reprogramming and succinate production. Finally, activation of PKM2 by TEPP-46 in vivo inhibited LPS and Salmonella typhimurium-induced IL-1β production, whilst boosting production of IL-10. PKM2 is therefore a critical determinant of macrophage activation by LPS, promoting the inflammatory response.

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“…Although diminished, these paracrine factors were still produced at high levels, suggesting that paracrine secretion by MSCs was not greatly affected by inhibition of their mitochondrial function ( Figures E3B and E3C). M1 proinflammatory macrophages have been shown to use glycolytic metabolism (31). Vats and colleagues highlighted the importance of mitochondrial oxidative phosphorylation in the induction of M2-type macrophages through IL-4 signaling.…”

“…Vats and colleagues showed the importance of mitochondrial oxidative phosphorylation in the induction of IL-4-induced antiinflammatory M2 macrophage polarization (30). Indeed, glucose metabolism is intrinsically linked to a macrophage activation state with M1 proinflammatory macrophages using glycolysis (31).…”

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“…113 Ageing, senescence, and bioenergetic sources O'Neill highlighted the prominence to the 'Warburg effect' in context to immune responses and the role in the pathogenesis of immune-mediated disorders, such as diabetes and atherosclerosis. [114][115][116] Extrapolating from Warburg's original observations that tumour cells undergo a bioenergetic switch (permissive for survival and proliferation), to aerobic glycolysis, we now appreciate that such bioenergetic switch occurs in the ageing and early AMD RPE. The Warburg effect rapidly provides ATP and enhances metabolic pathways to support immune cell function.…”

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“…Cells were cultured for 7-10 d to allow differentiation prior to experimentation. CS57BL/6 (Harlan) mice and IL-1R 2/2 mice (CS57BL/6 background; The Jackson Laboratory), kindly donated by Prof. Kingston Mills (School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin), were bred under specific pathogen-free conditions, and BMDM were isolated and cultured as previously described (6,7). Cells were differentiated until day 5, after which they were lifted using 10 mM EDTA and plated for experimentation.…”

“…Increased succinate results in impaired activity of prolylhydroxylases, allowing stabilization of the transcription factor hypoxia inducible factor-1a and leading to transcription of Il-1b and production of mature IL1b (6, 7). Molecular determinants of this significant change in metabolism are being investigated as potential targets for manipulation in this important pathway (7).…”