Trends in Immunology
Volume 41, Issue 2, February 2020, Pages 93-94
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ACLY-matizing Macrophages to Histone Modification during Immunometabolic Reprogramming

https://doi.org/10.1016/j.it.2019.12.009Get rights and content

Metabolic reprogramming in macrophages supports effector functions and differs depending on the activating stimulus. Lauterbach et al. now show that early metabolic alterations in macrophages driven by LPS signaling serve to increase the acetyl-CoA pool via citrate metabolism by the ATP-citrate lyase (ACLY), leading to histone acetylation and regulation of TLR-driven gene expression.

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Acknowledgments

This work was supported by funding from the Wellcome Trust, Irish Research Council, and the European Research Council.

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    Cytosol citrate is cleaved by ATP citrate lyase (ACLY) into acetyl-CoA and OA [14]. Acetyl-CoA is an essential precursor for histone acetylation [15]. An increasing body of evidence suggests that histone acetylation is involved in the activation of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome [16,17].

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    Similar to statins, treatment with bempedoic acid reduces CRP levels (Laufs et al., 2019; Ruscica et al., 2020), thus suggesting that the immunomodulatory effect could depend on the inhibition of cholesterol biosynthesis in the liver and the reduction of lipoprotein burden. ACLY has been recently shown to be critical also in contributing the acetyl-CoA pool required for histone acetylation and the regulation of TLR-driven gene expression after LPS stimulation (Lauterbach et al., 2019; Williams and O'Neill, 2020). This implies that approaches able to target ACLY specifically in macrophages in the atherosclerotic plaque could reduce their activation.

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