RUVBL1/2 Complex Regulates Pro-Inflammatory Responses in Macrophages via Regulating Histone H3K4 Trimethylation

  • Front Immunol. 2021 Jun 4:12:679184. doi: 10.3389/fimmu.2021.679184.
Rui Zhang  1  2 ,  Chris Y Cheung  1  2 ,  Sang-Uk Seo  3 ,  Hang Liu  4 ,  Lakhansing Pardeshi  5  6 ,  Koon Ho Wong  5  7 ,  Larry M C Chow  1  2 ,  Mary P Chau  1  2 ,  Yixiang Wang  1  2 ,  Ah Ra Lee  3 ,  Woon Yong Kwon  8 ,  Sheng Chen  9 ,  Bill Kwan-Wai Chan  1 ,  Kenneth Wong  10 ,  Richard K W Choy  10 ,  Ben C B Ko  1  2
Affiliations
  • 1. Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China.
  • 2. State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hong Kong, China.
  • 3. Department of Microbiology, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
  • 4. The University Research Facility in Chemical and Environmental Analysis, The Hong Kong Polytechnic University, Hong Kong, China.
  • 5. Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau.
  • 6. Genomics and Bioinformatics Core, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau.
  • 7. Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau.
  • 8. Department of Emergency Medicine, Seoul National University College of Medicine, Seoul, South Korea.
  • 9. Department of Infectious Diseases and Public Health, The City University of Hong Kong, Hong Kong, China.
  • 10. Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, China.
PMID: 34276666 DOI: 10.3389/fimmu.2021.679184
Abstract

Macrophages play an important role in the host defense mechanism. In response to Infection, macrophages activate a genetic program of pro-inflammatory response to kill any invading pathogen, and initiate an adaptive immune response. We have identified RUVBL2 - an ATP-binding protein belonging to the AAA+ (ATPase associated with diverse cellular activities) superfamily of ATPases - as a novel regulator in pro-inflammatory response of macrophages. Gene knockdown of Ruvbl2, or pharmacological inhibition of RUVBL1/2 activity, compromises type-2 nitric oxide synthase (Nos2) gene expression, nitric oxide production and anti-bacterial activity of mouse macrophages in response to lipopolysaccharides (LPS). RUVBL1/2 inhibitor similarly inhibits pro-inflammatory response in human monocytes, suggesting functional conservation of RUVBL1/2 in humans. Transcriptome analysis further revealed that major LPS-induced pro-inflammatory pathways in macrophages are regulated in a RUVBL1/2-dependent manner. Furthermore, RUVBL1/2 inhibition significantly reduced the level of histone H3K4me3 at the promoter region of Nos2 and Il6, two prototypical pro-inflammatory genes, and diminished the recruitment of NF-kappaB to the corresponding enhancers. Our study reveals RUVBL1/2 as an integral component of macrophage pro-inflammatory responses through epigenetic regulations, and the therapeutic potentials of RUVBL1/2 inhibitors in the treatment of diseases caused by aberrant activation of pro-inflammatory pathways.

Keywords
H3K4 trimethylation; RUVBL1/2; epigenetic modulation; macrophages; pro-inflammatory.
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