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. 2022 Feb;111(2):327-336.
doi: 10.1002/JLB.2MR1021-260R. Epub 2021 Nov 23.

The histone deacetylase Hdac7 supports LPS-inducible glycolysis and Il-1β production in murine macrophages via distinct mechanisms

Divya Ramnath  1   2 , Kaustav Das Gupta  1   2 , Yizhuo Wang  1   2 , Rishika Abrol  1   2 , James E B Curson  1   2 , Junxian Lim  1   3 , Robert C Reid  1   3 , Ashley Mansell  4 , Antje Blumenthal  5 , Denuja Karunakaran  1   2 , David P Fairlie  1   2   3 , Matthew J Sweet  1   2
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The histone deacetylase Hdac7 supports LPS-inducible glycolysis and Il-1β production in murine macrophages via distinct mechanisms

Divya Ramnath et al. J Leukoc Biol. 2022 Feb.

Abstract

TLRs reprogram macrophage metabolism, enhancing glycolysis and promoting flux through the tricarboxylic acid cycle to enable histone acetylation and inflammatory gene expression. The histone deacetylase (HDAC) family of lysine deacetylases regulates both TLR-inducible glycolysis and inflammatory responses. Here, we show that the TLR4 agonist LPS, as well as agonists of other TLRs, rapidly increase enzymatic activity of the class IIa HDAC family (HDAC4, 5, 7, 9) in both primary human and murine macrophages. This response was abrogated in murine macrophages deficient in histone deacetylase 7 (Hdac7), highlighting a selective role for this specific lysine deacetylase during immediate macrophage activation. With the exception of the TLR3 agonist polyI:C, TLR-inducible activation of Hdac7 enzymatic activity required the MyD88 adaptor protein. The rapid glycolysis response, as assessed by extracellular acidification rate, was attenuated in Hdac7-deficient mouse macrophages responding to submaximal LPS concentrations. Surprisingly however, reconstitution of these cells with either wild-type or an enzyme-dead mutant of Hdac7 enhanced LPS-inducible glycolysis, whereas only the former promoted production of the inflammatory mediators Il-1β and Ccl2. Thus, Hdac7 enzymatic activity is required for TLR-inducible production of specific inflammatory mediators, whereas it acts in an enzyme-independent fashion to reprogram metabolism in macrophages responding to submaximal LPS concentrations. Hdac7 is thus a bifurcation point for regulated metabolism and inflammatory responses in macrophages. Taken together with existing literature, our findings support a model in which submaximal and maximal activation of macrophages via TLR4 instruct glycolysis through distinct mechanisms, leading to divergent biological responses.

Keywords: LPS; TLR; cell metabolism; class IIa HDAC; inflammation; innate immunity.

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References

REFERENCES

    1. Kawasaki T and Kawai T Toll-like receptor signaling pathways. Front Immunol. 2014; 5:461.
    1. O'Neill LA, Golenbock D, and Bowie AG The history of Toll-like receptors - redefining innate immunity. Nat Rev Immunol. 2013; 13:453-460.
    1. Balka KR and De Nardo D Understanding early TLR signaling through the Myddosome. J Leukoc Biol. 2019; 105:339-351.
    1. Rossol M, Heine H, Meusch U, et al. LPS-induced cytokine production in human monocytes and macrophages. Crit Rev Immunol. 2011; 31:379-446.
    1. Luo L, Bokil NJ, Wall AA, et al. SCIMP is a transmembrane non-TIR TLR adaptor that promotes proinflammatory cytokine production from macrophages. Nat Commun. 2017; 8:14133.

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