Trichostatin A modulates the macrophage phenotype by enhancing autophagy to reduce inflammation during polymicrobial sepsis

被引:38
作者
Cui, Shu-Nan [1 ,3 ]
Chen, Zhao-Yuan [1 ,3 ]
Yang, Xiao-Bo [1 ,3 ]
Chen, Lin [2 ,3 ]
Yang, Yi-Yi [2 ,3 ]
Pan, Shang-Wen [1 ,3 ]
Wang, Ya-Xin [1 ,3 ]
Xu, Ji-Qian [1 ,3 ]
Zhou, Ting [1 ,3 ]
Xiao, Hai-Rong [2 ,3 ]
Qin, Lu [2 ,3 ]
Yuan, Shi-Ying [1 ,3 ]
Shang, You [1 ,3 ]
机构
[1] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Crit Care Med, Wuhan, Hubei, Peoples R China
[2] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Anesthesiol, Wuhan, Hubei, Peoples R China
[3] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Inst Anesthesiol & Crit Care Med, Wuhan, Hubei, Peoples R China
基金
中国国家自然科学基金;
关键词
Sepsis; Macrophage polarization; Autophagy; Trichostatin A; Inflammation; HISTONE DEACETYLASE INHIBITORS; CECAL LIGATION; ACTIVATION; POLARIZATION; INJURY; MTOR; INCREASES; FEATURES; LIVER; ACID;
D O I
10.1016/j.intimp.2019.105973
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Sepsis is a syndrome of life-threatening organ dysfunction caused by dysregulated host responses to infection. Macrophage polarization is a key process involved in the pathogenesis of sepsis. Recent evidence has demonstrated that autophagy participates in the regulation of macrophage polarization in different phases of inflammation. Here, we investigated whether trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, promotes the macrophage M2 phenotype by enhancing autophagy to counteract excessive inflammation in a cecal ligation and puncture (CLP) mouse model. TSA stimulation increased the proportions of M2 marker (CD206, CD124 and CD23)-labeled RAW264.7 macrophages. Furthermore, with increasing TSA doses, autophagy was enhanced gradually. Interestingly, the autophagy activator rapamycin (Rap), also known as an mTOR inhibitor, unexpectedly decreased the proportions of M2 marker-labeled macrophages. However, TSA treatment reversed the Rap-induced decreases in CD206-labeled macrophages. Next, we stimulated different groups of RAW264.7 cells with the autophagy inhibitors MHY1485 or 3-methyladenine (3-MA). Inhibition of autophagy at any stage in the process suppressed TSA-induced macrophage M2 polarization, but the effect was not associated with mTOR activity. In vivo, TSA administration promoted peritoneal macrophage M2 polarization, increased LC3 II expression, attenuated sepsis-induced organ (lung, liver and kidney) injury, and altered systemic inflammatory cytokine secretion. However, 3-MA abolished the protective effects of TSA in CLP mice and decreased the number of M2 peritoneal macrophages. Therefore, TSA promotes the macrophage M2 phenotype by enhancing autophagy to reduce systemic inflammation and ultimately improves the survival of mice with polymicrobial sepsis.
引用
收藏
页数:9
相关论文
共 37 条
[11]   The recognition and management of sepsis and septic shock: a guide for non-intensivists [J].
Keeley, Alexander ;
Hine, Paul ;
Nsutebu, Emmanuel .
POSTGRADUATE MEDICAL JOURNAL, 2017, 93 (1104) :626-634
[12]   Trichostatin A Protects Liver against Septic Injury through Inhibiting Toll-Like Receptor Signaling [J].
Kim, So-Jin ;
Park, Jin-Sook ;
Lee, Do-Won ;
Lee, Sun-Mee .
BIOMOLECULES & THERAPEUTICS, 2016, 24 (04) :387-394
[13]   HDAC inhibition helps post-MI healing by modulating macrophage polarization [J].
Kimbrough, Denise ;
Wang, Sabina H. ;
Wright, Lillianne H. ;
Mani, Santhosh K. ;
Kasiganesan, Harinath ;
LaRue, Amanda C. ;
Cheng, Qi ;
Nadig, Satish N. ;
Atkinson, Carl ;
Menick, Donald R. .
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 2018, 119 :51-63
[14]   Polarization of M2 macrophages requires Lamtor1 that integrates cytokine and amino-acid signals [J].
Kimura, Tetsuya ;
Nada, Shigeyuki ;
Takegahara, Noriko ;
Okuno, Tatsusada ;
Nojima, Satoshi ;
Kang, Sujin ;
Ito, Daisuke ;
Morimoto, Keiko ;
Hosokawa, Takashi ;
Hayama, Yoshitomo ;
Mitsui, Yuichi ;
Sakurai, Natsuki ;
Sarashina-Kida, Hana ;
Nishide, Masayuki ;
Maeda, Yohei ;
Takamatsu, Hyota ;
Okuzaki, Daisuke ;
Yamada, Masaki ;
Okada, Masato ;
Kumanogoh, Atsushi .
NATURE COMMUNICATIONS, 2016, 7
[15]   Transcriptional regulation of macrophage polarization: enabling diversity with identity [J].
Lawrence, Toby ;
Natoli, Gioacchino .
NATURE REVIEWS IMMUNOLOGY, 2011, 11 (11) :750-761
[16]   Impaired macrophage autophagy increases the immune response in obese mice by promoting proinflammatory macrophage polarization [J].
Liu, Kun ;
Zhao, Enpeng ;
Ilyas, Ghulam ;
Lalazar, Gadi ;
Lin, Yu ;
Haseeb, Muhammad ;
Tanaka, Kathryn E. ;
Czaja, Mark J. .
AUTOPHAGY, 2015, 11 (02) :271-284
[17]   Macrophage Polarization in Inflammatory Diseases [J].
Liu, Yan-Cun ;
Zou, Xian-Biao ;
Chai, Yan-Fen ;
Yao, Yong-Ming .
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES, 2014, 10 (05) :520-529
[18]   Novel macrophage polarization model: from gene expression to identification of new anti-inflammatory molecules [J].
Lopez-Castejon, Gloria ;
Baroja-Mazo, Alberto ;
Pelegrin, Pablo .
CELLULAR AND MOLECULAR LIFE SCIENCES, 2011, 68 (18) :3095-3107
[19]   Autophagy and Cellular Immune Responses [J].
Ma, Yuting ;
Galluzzi, Lorenzo ;
Zitvogel, Laurence ;
Kroemer, Guido .
IMMUNITY, 2013, 39 (02) :211-227
[20]   An Official American Thoracic Society Workshop Report: Features and Measurements of Experimental Acute Lung Injury in Animals [J].
Matute-Bello, Gustavo ;
Downey, Gregory ;
Moore, Bethany B. ;
Groshong, Steve D. ;
Matthay, Michael A. ;
Slutsky, Arthur S. ;
Kuebler, Wolfgang M. ;
Chilvers, Edwin R. ;
Doerschuck, Claire ;
Dreyfuss, Didier ;
Eichacker, Peter Q. ;
Elias, Jack A. ;
Esteban, Andres ;
Ferguson, Niall D. ;
Glenny, Robb W. ;
Henson, Peter ;
Lorente, Jose A. ;
Martin, Thomas R. ;
Nick, Jerry A. ;
Rimensberger, Peter ;
Uhlig, Stefan ;
Van Der Poll, Tom ;
Villar, Jesus .
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 2011, 44 (05) :725-738