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Weill Cornell Medical College, Hospital for Special Surgery

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Immunity, Available online 11 July 2019 | https://doi.org/10.1016/j.immuni.2019.06.005 The Cytokine TNF Promotes Transcription Factor SREBP Activity and Binding to Inflammatory Genes to Activate Macrophages and Limit Tissue Repair

Anthony Kusnadi^1,3,6, Sung Ho Park^3,5,6, Ruoxi Yuan³, Tania Pannellini³, Eugenia Giannopoulou^3,4, David Oliver³, Theresa Lu^1,3, Kyung-Hyun Park-Min^2,3,*, Lionel B. Ivashkiv^1,3,7,*

¹ Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA
² BCMB Allied Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA
³ Research Institute and the David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021, USA
⁴ Biological Sciences Department, New York City College of Technology, City University of New York, Brooklyn, NY 11201, USA
⁵ School of Life Sciences, Ulsan National Institute of Science & Technology (UNIST), Ulsan 44919, Korea
⁶These authors contributed equally
⁷Lead Contact

^*Corresponding author : Kyung-Hyun Park-Min, Lionel B. Ivashkiv

Abstract

Cytokine tumor necrosis factor (TNF)-mediated macrophage polarization is important for inflammatory disease pathogenesis, but the mechanisms regulating polarization are not clear. We performed transcriptomic and epigenomic analysis of the TNF response in primary human macrophages and revealed late-phase activation of SREBP2, the master regulator of cholesterol biosynthesis genes. TNF stimulation extended the genomic profile of SREBP2 occupancy to include binding to and activation of inflammatory and interferon response genes independently of its functions in sterol metabolism. Genetic ablation of SREBP function shifted the balance of macrophage polarization from an inflammatory to a reparative phenotype in peritonitis and skin wound healing models. Genetic ablation of SREBP activity in myeloid cells or topical pharmacological inhibition of SREBP improved skin wound healing under homeostatic and chronic inflammatory conditions. Our results identify a function and mechanism of action for SREBPs in augmenting TNF-induced macrophage activation and inflammation and open therapeutic avenues for promoting wound repair.

Keywords : TNF; SREBP2; macrophages; transcriptomics; epigenomics; cholesterol; wound healing; macrophage polarization; tissue repair; inflammation

논문정보

형식Research article
게재일2019년 07월 (BRIC 등록일 2019-07-23)
연구진국내+국외 연구진
분야 생명과학 > 면역학

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