Institute for Molecular Bioscience (IMB), IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland, Australia.
Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, Australia.
J Leukoc Biol. 2022 Feb;111(2):327-336. doi: 10.1002/JLB.2MR1021-260R. Epub 2021 Nov 23.
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.
TLRs 重新编程巨噬细胞代谢，增强糖酵解并促进三羧酸循环通量，以实现组蛋白乙酰化和炎症基因表达。赖氨酸去乙酰化酶 (HDAC) 家族的组蛋白去乙酰酶调节 TLR 诱导的糖酵解和炎症反应。在这里，我们表明 TLR4 激动剂 LPS 以及其他 TLR 的激动剂，可迅速增加原发性人和鼠巨噬细胞中 IIa 类 HDAC 家族（HDAC4、5、7、9）的酶活性。在缺乏组蛋白脱乙酰酶 7 (Hdac7) 的鼠巨噬细胞中，这种反应被消除，突出了这种特定赖氨酸脱乙酰酶在巨噬细胞即刻激活过程中的选择性作用。除 TLR3 激动剂 polyI:C 外，Hdac7 酶活性的 TLR 诱导激活需要 MyD88 衔接蛋白。通过细胞外酸化率评估的快速糖酵解反应在对亚最大 LPS 浓度做出反应的 Hdac7 缺陷型鼠巨噬细胞中减弱。然而，令人惊讶的是，用野生型或酶失活突变体的 Hdac7 重建这些细胞增强了 LPS 诱导的糖酵解，而只有前者促进了炎症介质 Il-1β 和 Ccl2 的产生。因此，Hdac7 酶活性是 TLR 诱导产生特定炎症介质所必需的，而在对亚最大 LPS 浓度做出反应的巨噬细胞中，它以非酶依赖的方式作用于代谢重编程。Hdac7 是巨噬细胞中调节代谢和炎症反应的分支点。结合现有文献，我们的发现支持这样一种模型，即通过 TLR4 对巨噬细胞进行亚最大和最大激活通过不同的机制指导糖酵解，从而导致不同的生物学反应。
