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

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.

MicroRNAs Promote the Progression of Sepsis-Induced Cardiomyopathy and Neurovascular Dysfunction Through Upregulation of NF-kappaB Signaling Pathway-Associated HDAC7/ACTN4

“…However, a previous study found that HDAC7 is involved in the regulation of apoptosis ( 80 ). The enzymatic activity of HDAC7 is essential for TLR-induced production of inflammatory mediators and is involved in the inflammatory response ( 81 ). ACTN4 is involved in the inflammatory or immune response in the lungs ( 82 ).…”

Assessing the effect of interaction between gut microbiome and inflammatory bowel disease on the risks of depression

“…Moreover, we detected several candidate genes for depression phenotypes, such as HDAC7 , GPM6A , VDR , and QRICH1 . HDAC7 is a major histone deacetylase, which can drive macrophage-mediated inflammatory response and increase the proinflammatory mediators IL-1β and Ccl2 ( Das Gupta et al, 2020 ; Ramnath et al, 2021 ; Shakespear et al, 2013 ). GPM6A promotes the formation of synapses and is involved in the brain signaling pathways of psychiatric disorders such as depression and schizophrenia ( Aparicio et al, 2020 ; Fuchsova et al, 2015 ).…”

Silicon switch: Carbon–silicon Bioisosteric replacement as a strategy to modulate the selectivity, physicochemical, and drug‐like properties in anticancer pharmacophores

“…Histone deacetylases (HDACs) are a family of enzymes responsible for catalyzing the removal of acetyl functional groups from the lysine residues of both histone and nonhistone proteins (Ramnath et al, 2022; Yildiz & Yildiz, 2022). There are 18 histone deacetylases in humans that involve either zinc‐ or NAD + ‐dependent mechanisms to deacetylate acetyl lysine substrates (Porter & Christianson, 2019; Ramnath et al, 2022; Yildiz & Yildiz, 2022).…”

“…Histone deacetylases (HDACs) are a family of enzymes responsible for catalyzing the removal of acetyl functional groups from the lysine residues of both histone and nonhistone proteins (Ramnath et al, 2022; Yildiz & Yildiz, 2022). There are 18 histone deacetylases in humans that involve either zinc‐ or NAD + ‐dependent mechanisms to deacetylate acetyl lysine substrates (Porter & Christianson, 2019; Ramnath et al, 2022; Yildiz & Yildiz, 2022). While the removal of histone acetyl epigenetic modification by HDACs regulates chromatin structure and transcription, the deacetylation of nonhistones controls diverse cellular processes (Ramnath et al, 2022; Yildiz & Yildiz, 2022).…”

“…There are 18 histone deacetylases in humans that involve either zinc‐ or NAD + ‐dependent mechanisms to deacetylate acetyl lysine substrates (Porter & Christianson, 2019; Ramnath et al, 2022; Yildiz & Yildiz, 2022). While the removal of histone acetyl epigenetic modification by HDACs regulates chromatin structure and transcription, the deacetylation of nonhistones controls diverse cellular processes (Ramnath et al, 2022; Yildiz & Yildiz, 2022). As such, histone deacetylase inhibitors were proven to be able to reverse the activation of tumor suppressor genes, resulting in the inhibition of the viability and malignant proliferation of tumor cells (Hai et al, 2021; Meyer‐Almes, 2019; Sanaei & Kavoosi, 2019).…”