2. Academic Validation
  3. Histone Deacetylase 3 Couples Mitochondria to Drive IL-1β-Dependent Inflammation by Configuring Fatty Acid Oxidation

Histone Deacetylase 3 Couples Mitochondria to Drive IL-1β-Dependent Inflammation by Configuring Fatty Acid Oxidation

  • Mol Cell. 2020 Oct 1;80(1):43-58.e7. doi: 10.1016/j.molcel.2020.08.015.
Zhexu Chi 1,  Sheng Chen 2,  Ting Xu 1,  Wenxuan Zhen 3,  Weiwei Yu 1,  Danlu Jiang 1,  Xingchen Guo 4,  Zhen Wang 1,  Kailian Zhang 1,  Mobai Li 1,  Jian Zhang 1,  Hui Fang 1,  Dehang Yang 1,  Qizhen Ye 1,  Xuyan Yang 5,  Hui Lin 6,  Fan Yang 3,  Xue Zhang 7,  Di Wang 8
Affiliations

Affiliations

  • 1 Institute of Immunology, and Department of Orthopaedic Surgery of the Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China.
  • 2 Institute of Immunology, and Department of Orthopaedic Surgery of the Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China; Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China.
  • 3 Department of Biophysics, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China.
  • 4 State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, P.R. China.
  • 5 Department of Rheumatology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China.
  • 6 Department of General Surgery of the Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China.
  • 7 Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China.
  • 8 Institute of Immunology, and Department of Orthopaedic Surgery of the Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. Electronic address: diwang@zju.edu.cn.
PMID: 32937100 DOI: 10.1016/j.molcel.2020.08.015
Abstract

Immune cell function depends on specific metabolic programs dictated by mitochondria, including nutrient oxidation, macromolecule synthesis, and post-translational modifications. Mitochondrial adaptations have been linked to acute and chronic inflammation, but the metabolic cues and precise mechanisms remain unclear. Here we reveal that histone deacetylase 3 (HDAC3) is essential for shaping mitochondrial adaptations for IL-1β production in macrophages through non-histone deacetylation. In vivo, HDAC3 promoted lipopolysaccharide-induced acute inflammation and high-fat diet-induced chronic inflammation by enhancing NLRP3-dependent Caspase-1 activation. HDAC3 configured the lipid profile in stimulated macrophages and restricted fatty acid oxidation (FAO) supported by exogenous fatty acids for mitochondria to acquire their adaptations and depolarization. Rather than affecting nuclear gene expression, HDAC3 translocated to mitochondria to deacetylate and inactivate an FAO Enzyme, mitochondrial trifunctional Enzyme subunit α. HDAC3 may serve as a controlling node that balances between acquiring mitochondrial adaptations and sustaining their fitness for IL-1β-dependent inflammation.

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