Regulation of IL-4-induced human macrophage polarization by acetyl-CoA and AMP-activated protein kinase

• Applicant: Privatdozent Dr. Dmitry Namgaladze
• Subject Area: Public Health, Healthcare Research, Social and Occupational Medicine ; Biochemistry ; Immunology ; Cell Biology
• Term: from 2014 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 260847914

Macrophages respond to pro- versus anti-inflammatory stimuli (macrophage polarization) by altering their metabolism. In turn, intermediate metabolites regulate intracellular signaling and gene expression. Thus, acetyl-CoA, besides its role in energy generation by driving the citrate cycle, is a substrate for protein and histone acetylation. ATP citrate lyase (ACLY), an enzyme responsible for cytosolic acetyl-CoA generation, support gene expression through histone acetylation in responses to altered nutrient levels in cancer cells and adipocytes, but also to the cytokine IL-4 in murine macrophages. Our preliminary data show an IL-4-stimulated expression of arachidonate 15-lipoxygenase (ALOX15) to be sensitive to ACLY inhibition. However, the impact of ACLY and acetyl-CoA on IL-4-induced human macrophage polarization remains unclear. Furthermore, we have previously shown that AMP-dependent protein kinase (AMPK) - mediated inhibition of ALOX15 expression in IL-4-stimulated macrophages may partly occur through altered histone acetylation. In this proposal we aim to elucidate the influence of ACLY-driven acetyl-CoA generation on human macrophage polarization in response to IL-4. We postulate that ACLY, by physically associating with gene regulatory elements on chromatin, may locally regulate histone acetylation on a subset of IL-4-responsive genes. Second we reveal an altered pattern of protein acetylation, dependent on ACLY-driven acetyl-CoA. This will be address in a proteomic screen. Third, we investigate the influence of AMPK on protein acetylation. We suggest that AMPK inhibits the activity of ACLY, thereby eliciting changes of histone acetylation and thus, gene expression. Our study adds to understand how metabolism and, in particular, acetyl-CoA generation, connects to macrophage polarization.

• DFG Programme: Research Grants