Activation of JUN in fibroblasts promotes pro-fibrotic programme and modulates protective immunity

被引:91
作者
Cui, Lu [1 ]
Chen, Shih-Yu [2 ]
Lerbs, Tristan [1 ]
Lee, Jin-Wook [3 ]
Domizi, Pablo [1 ]
Gordon, Sydney [4 ]
Kim, Yong-hun [1 ]
Nolan, Garry [5 ]
Betancur, Paola [6 ]
Wernig, Gerlinde [1 ]
机构
[1] Stanford Univ, Dept Pathol, Sch Med, Inst Stem Cell Biol & Regenerat Med ISCBRM, Stanford, CA 94305 USA
[2] Acad Sinica, Inst Biomed Sci, Taipei 11529, Taiwan
[3] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA
[4] Orca Biosyst, 3475 Edison Way,Suite B, Menlo Pk, CA 94025 USA
[5] Stanford Univ, Dept Microbiol & Immunol, Baxter Labs, Sch Med, Stanford, CA 94305 USA
[6] Univ Calif San Francisco, Dept Radiat Oncol, San Francisco, CA 94143 USA
关键词
FUTURE-DIRECTIONS; PULMONARY; MACROPHAGES; CELLS; CD47; PHAGOCYTOSIS; EXPRESSION; TARGET; IL-6; SKIN;
D O I
10.1038/s41467-020-16466-4
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The transcription factor JUN is highly expressed in pulmonary fibrosis. Its induction in mice drives lung fibrosis, which is abrogated by administration of anti-CD47. Here, we use high-dimensional mass cytometry to profile protein expression and secretome of cells from patients with pulmonary fibrosis. We show that JUN is activated in fibrotic fibroblasts that expressed increased CD47 and PD-L1. Using ATAC-seq and ChIP-seq, we found that activation of JUN rendered promoters and enhancers of CD47 and PD-L1 accessible. We further detect increased IL-6 that amplified JUN-mediated CD47 enhancer activity and protein expression. Using an in vivo mouse model of fibrosis, we found two distinct mechanisms by which blocking IL-6, CD47 and PD-L1 reversed fibrosis, by increasing phagocytosis of profibrotic fibroblasts and by eliminating suppressive effects on adaptive immunity. Our results identify specific immune mechanisms that promote fibrosis and suggest a therapeutic approach that could be used alongside conventional anti-fibrotics for pulmonary fibrosis. Fibroblast contributions to lung fibrosis and in particular their crosstalk with immune cells in the lung are incompletely understood. Here, the authors show an overall immune suppressive environment transcriptionally controlled and maintained by fibroblasts in lung fibrosis with possible therapeutic implications.
引用
收藏
页数:14
相关论文
共 58 条
[1]   C2c2 is a single-component programmable RNA-guided RNA-targeting CRISPR effector [J].
Abudayyeh, Omar O. ;
Gootenberg, Jonathan S. ;
Konermann, Silvana ;
Joung, Julia ;
Slaymaker, Ian M. ;
Cox, David B. T. ;
Shmakov, Sergey ;
Makarova, Kira S. ;
Semenova, Ekaterina ;
Minakhin, Leonid ;
Severinov, Konstantin ;
Regev, Aviv ;
Lander, Eric S. ;
Koonin, Eugene V. ;
Zhang, Feng .
SCIENCE, 2016, 353 (6299)
[2]   A CD47-associated super-enhancer links pro-inflammatory signalling to CD47 upregulation in breast cancer [J].
Betancur, Paola A. ;
Abraham, Brian J. ;
Yiu, Ying Y. ;
Willingham, Stephen B. ;
Khameneh, Farnaz ;
Zarnegar, Mark ;
Kuo, Angera H. ;
McKenna, Kelly ;
Kojima, Yoko ;
Leeper, Nicholas J. ;
Ho, Po ;
Gip, Phung ;
Swigut, Tomek ;
Sherwood, Richard I. ;
Clarke, Michael F. ;
Somlo, George ;
Young, Richard A. ;
Weissman, Irving L. .
NATURE COMMUNICATIONS, 2017, 8
[3]   Flow Cytometry Reveals Similarities Between Lung Macrophages in Humans and Mice [J].
Bharat, Ankit ;
Bhorade, Sangeeta M. ;
Morales-Nebreda, Luisa ;
McQuattie-Pimentel, Alexandra C. ;
Soberanes, Saul ;
Ridge, Karen ;
DeCamp, Malcolm M. ;
Mestan, Karen K. ;
Perlman, Harris ;
Budinger, G. R. Scott ;
Misharin, Alexander V. .
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 2016, 54 (01) :147-149
[4]   Future Directions in Idiopathic Pulmonary Fibrosis Research [J].
Blackwell, Timothy S. ;
Tager, Andrew M. ;
Borok, Zea ;
Moore, Bethany B. ;
Schwartz, David A. ;
Anstrom, Kevin J. ;
Bar-Joseph, Ziv ;
Bitterman, Peter ;
Blackburn, Michael R. ;
Bradford, William ;
Brown, Kevin K. ;
Chapman, Harold A. ;
Collard, Harold R. ;
Cosgrove, Gregory P. ;
Deterding, Robin ;
Doyle, Ramona ;
Flaherty, Kevin R. ;
Garcia, Christine Kim ;
Hagood, James S. ;
Henke, Craig A. ;
Herzog, Erica ;
Hogaboam, Cory M. ;
Horowitz, Jeffrey C. ;
King, Talmadge E., Jr. ;
Loyd, James E. ;
Lawson, William E. ;
Marsh, Clay B. ;
Noble, Paul W. ;
Noth, Imre ;
Sheppard, Dean ;
Olsson, Julie ;
Ortiz, Luis A. ;
O'Riordan, Thomas G. ;
Oury, Tim D. ;
Raghu, Ganesh ;
Roman, Jesse ;
Sime, Patricia J. ;
Sisson, Thomas H. ;
Tschumperlin, Daniel ;
Violette, Shelia M. ;
Weaver, Timothy E. ;
Wells, Rebecca G. ;
White, Eric S. ;
Kaminski, Naftali ;
Martinez, Fernando J. ;
Wynn, Thomas A. ;
Thannickal, Victor J. ;
Eu, Jerry P. .
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2014, 189 (02) :214-222
[5]  
Buenrostro Jason D, 2015, Curr Protoc Mol Biol, V109, DOI 10.1002/0471142727.mb2129s109
[6]   MYC regulates the antitumor immune response through CD47 and PD-L1 [J].
Casey, Stephanie C. ;
Tong, Ling ;
Li, Yulin ;
Do, Rachel ;
Walz, Susanne ;
Fitzgerald, Kelly N. ;
Gouw, Arvin M. ;
Baylot, Virginie ;
Guetgemann, Ines ;
Eilers, Martin ;
Felsher, Dean W. .
SCIENCE, 2016, 352 (6282) :227-231
[7]   PD-1 up-regulation on CD4+ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production [J].
Celada, Lindsay J. ;
Kropski, Jonathan A. ;
Herazo-Maya, Jose D. ;
Luo, Weifeng ;
Creecy, Amy ;
Abad, Andrew T. ;
Chioma, Ozioma S. ;
Lee, Grace ;
Hassell, Natalie E. ;
Shaginurova, Guzel, I ;
Wang, Yufen ;
Johnson, Joyce E. ;
Kerrigan, Amy ;
Mason, Wendi R. ;
Baughman, Robert P. ;
Ayers, Gregory D. ;
Bernard, Gordon R. ;
Culver, Daniel A. ;
Montgomery, Courtney G. ;
Maher, Toby M. ;
Molyneaux, Philip L. ;
Noth, Imre ;
Mutsaers, Steven E. ;
Prele, Cecilia M. ;
Peebles, R. Stokes, Jr. ;
Newcomb, Dawn C. ;
Kaminski, Naftali ;
Blackwell, Timothy S. ;
Van Kaer, Luc ;
Drake, Wonder P. .
SCIENCE TRANSLATIONAL MEDICINE, 2018, 10 (460)
[8]   Oncogenic RAS Signaling Promotes Tumor Immunoresistance by Stabilizing PD-L1 mRNA [J].
Coelho, Matthew A. ;
Trecesson, Sophie de Carne ;
Rana, Sareena ;
Zecchin, Davide ;
Moore, Christopher ;
Molina-Arcas, Miriam ;
East, Philip ;
Spencer-Dene, Bradley ;
Nye, Emma ;
Barnouin, Karin ;
Snijders, Ambrosius P. ;
Lai, Wi S. ;
Blackshear, Perry J. ;
Downward, Julian .
IMMUNITY, 2017, 47 (06) :1083-+
[9]   INFLAMMATORY DISEASE T cell-targeted antibody reverses fibrosis [J].
Crunkhorn, Sarah .
NATURE REVIEWS DRUG DISCOVERY, 2016, 15 (08) :530-530
[10]   Distinct bone marrow-derived and tissue-resident macrophage lineages proliferate at key stages during inflammation [J].
Davies, Luke C. ;
Rosas, Marcela ;
Jenkins, Stephen J. ;
Liao, Chia-Te ;
Scurr, Martin J. ;
Brombacher, Frank ;
Fraser, Donald J. ;
Allen, Judith E. ;
Jones, Simon A. ;
Taylor, Philip R. .
NATURE COMMUNICATIONS, 2013, 4