Blocking IL-17A Promotes the Resolution of Pulmonary Inflammation and Fibrosis Via TGF-β1–Dependent and –Independent Mechanisms
Open accessAbstract
Pulmonary fibrosis is the pathologic basis for a variety of incurable human chronic lung diseases. IL-17A, a glycoprotein secreted from IL-17–producing cells, has recently been shown to be a proinflammatory cytokine involved in chronic inflammation and autoimmune disease. In this study, we report that IL-17A increased the synthesis and secretion of collagen and promoted the epithelial–mesenchymal transition in alveolar epithelial cells in a TGF-β1–dependent manner. Using in vivo fibrotic models, we found IL-17A expression to be elevated and IL-17A–associated signaling pathways to be activated in fibrotic lung tissues. Neutralization of IL-17A in vivo promoted the resolution of bleomycin-induced acute inflammation, attenuated pulmonary fibrosis, and increased survival. Additionally, IL-17A antagonism inhibited silica-induced chronic inflammation and pulmonary fibrosis. Targeting IL-17A resulted in a shift of the suppressive immune response in fibrotic lung tissue toward a Th1-type immune response, and it effectively induced autophagy, which promoted the autophagic degradation of collagen and autophagy-associated cell death. Moreover, IL-17A was found to attenuate the starvation-induced autophagy, and autophagy modulators regulated collagen degradation in the alveolar epithelial cells in a TGF-β1–independent manner. Administration of 3-methylamphetamine, an autophagy inhibitor, reversed the therapeutic efficacy of IL-17A antagonism in pulmonary fibrosis. Our studies indicate that IL-17A participates in the development and progression of pulmonary fibrosis in both TGF-β1–dependent and –independent manners and that the components of the IL-17A signaling pathway are potential therapeutic targets for the treatment of fibroproliferative lung diseases.
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Neutralization of IL-17 can reduce fibrosis in several animal models.
“neutralization of IL-17 can reduce fibrosis in several animal models (146, 147).”
From The Role of Immune and Inflammatory Cells in Idiopathic Pulmonary Fibrosis (2018) · cites this paper as [146]
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1 retracted
Blocking TLR2 Activity Attenuates Pulmonary Metastases of Tumor
Yang, H.-Z., Cui, B., Liu, H.-Z., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0006520 · Cited by 100 · see citing works
Self-citationRetractedEpithelial-Mesenchymal Transitions in Development and Disease
Thiery, J. P., Acloque, H., Huang, R. Y. J., & Nieto, M. A. (2009) · Cell · doi:10.1016/j.cell.2009.11.007 · Cited by 9,931 · see citing works
Methods in Mammalian Autophagy Research
Mizushima, N., Yoshimori, T., & Levine, B. (2010) · Cell · doi:10.1016/j.cell.2010.01.028 · Cited by 4,497 · see citing works
Cellular and molecular mechanisms of fibrosis
Wynn, T. (2008) · The Journal of Pathology · doi:10.1002/path.2277 · Cited by 4,495 · see citing works
A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17
Park, H., Li, Z., Yang, X. O., Chang, S. H., Nurieva, R., Wang, Y.-H., Wang, Y., Hood, L., Zhu, Z., Tian, Q., et al. (2005) · Nature Immunology · doi:10.1038/ni1261 · Cited by 4,265 · see citing works
Self-citationTGF-β-induced epithelial to mesenchymal transition
Xu, J., Lamouille, S., & Derynck, R. (2009) · Cell Research · doi:10.1038/cr.2009.5 · Cited by 2,804 · see citing works
Nathan, C., & Ding, A. (2010) · Cell · doi:10.1016/j.cell.2010.02.029 · Cited by 2,183 · see citing works
IL-17 family cytokines and the expanding diversity of effector T cell lineages
Weaver, C. T., Hatton, R. D., Mangan, P. R., & Harrington, L. E. (2007) · Annual Review of Immunology · doi:10.1146/annurev.immunol.25.022106.141557 · Cited by 1,842 · see citing works
Autophagy Suppresses Tumorigenesis through Elimination of p62
Mathew, R., Karp, C. M., Beaudoin, B., Vuong, N., Chen, G., Chen, H.-Y., Bray, K., Reddy, A., Bhanot, G. V., Gélinas, C., et al. (2009) · Cell · doi:10.1016/j.cell.2009.03.048 · Cited by 1,723 · see citing works
Autophagic cell death: the story of a misnomer
Kroemer, G., & Levine, B. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2529 · Cited by 1,453 · see citing works
The Beclin 1–VPS34 complex – at the crossroads of autophagy and beyond
Funderburk, S. F., Wang, Q. J., & Yue, Z. (2010) · Trends in Cell Biology · doi:10.1016/j.tcb.2010.03.002 · Cited by 778 · see citing works
Bleomycin and IL-1β–mediated pulmonary fibrosis is IL-17A dependent
Wilson, M. S., Madala, S. K., Ramalingam, T. R., Gochuico, B. R., Rosas, I. O., Cheever, A. W., & Wynn, T. A. (2010) · Journal of Experimental Medicine · doi:10.1084/jem.20092121 · Cited by 730 · see citing works
Salazar‐Roa, M., Carracedo, A., Salanueva, Í. J., Hernández‐Tiedra, S., Lorente, M., Egia, A., Vázquez, P., Blázquez, C., Torres, S., Garcia, S., et al. (2009) · Journal of Clinical Investigation · doi:10.1172/jci37948 · Cited by 686 · see citing works
Response to myocardial ischemia/reperfusion injury involves Bnip3 and autophagy
Hamacher-Brady, A., Brady, N. R., Logue, S. E., Sayen, M. R., Jinno, M., Kirshenbaum, L. A., Gottlieb, R. A., & Gustafsson, Å. B. (2007) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401936 · Cited by 609 · see citing works
Decoding Cell Death Signals in Inflammation and Immunity
Zitvogel, L., Kepp, O., & Kroemer, G. (2010) · Cell · doi:10.1016/j.cell.2010.02.015 · Cited by 558 · see citing works
T helper 2 cytokines inhibit autophagic control of intracellular Mycobacterium tuberculosis.
Harris, J., Haro, S. A. D., Master, S. S., Keane, J., Roberts, E. A., Delgado, M. A., & Deretic, V. (2007) · Immunity · doi:10.1016/j.immuni.2007.07.022 · Cited by 497 · see citing works
Li, L., Huang, L., Vergis, A. L., Ye, H., Bajwa, A., Narayan, V., Strieter, R. M., Rosin, D. L., & Okusa, M. D. (2009) · Journal of Clinical Investigation · doi:10.1172/jci38702 · Cited by 485 · see citing works
Leppkes, M., Becker, C., Ivanov, I. I., Hirth, S., Wirtz, S. J., Neufert, C. F., Pouly, S., Murphy, A. J., Valenzuela, D. M., Yancopoulos, G. D., et al. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.10.018 · Cited by 445 · see citing works
Blockade of Interleukin-17A Results in Reduced Atherosclerosis in Apolipoprotein E–Deficient Mice
Smith, E. E., Prasad, K.-M. R., Butcher, M. J., Dobrian, A. D., Kolls, J. K., Ley, K. F., & Galkina, E. (2010) · Circulation · doi:10.1161/circulationaha.109.924886 · Cited by 422 · see citing works
Intestinal fibrosis in IBD—a dynamic, multifactorial process
Rieder, F., & Fiocchi, C. (2009) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2009.31 · Cited by 342 · see citing works
Baldeviano, G. C., Barin, J. G., Talor, M. V., Srinivasan, S., Bedja, D., Zheng, D., Gabrielson, K., Iwakura, Y., Rose, N. R., & Cihakova, D. (2010) · Circulation Research · doi:10.1161/circresaha.109.213157 · Cited by 334 · see citing works
Kiyono, K., Suzuki, H. I., Matsuyama, H., Morishita, Y., Komuro, A., Kano, M. R., Sugimoto, K., & Miyazono, K. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-4401 · Cited by 285 · see citing works
Koesters, R., Kaissling, B., LeHir, M., Picard, N., Theilig, F., Gebhardt, R., Glick, A. B., Hähnel, B., Hosser, H., Gröne, H., et al. (2010) · American Journal Of Pathology · doi:10.2353/ajpath.2010.091012 · Cited by 271 · see citing works
Strategies for treating idiopathic pulmonary fibrosis
du Bois, R. M. (2010) · Nature Reviews Drug Discovery · doi:10.1038/nrd2958 · Cited by 246 · see citing works
Atabai, K., Jamé, S., Azhar, N., Kuo, A., Lam, M. P. Y., McKleroy, W., DeHart, G., Rahman, S., Xia, D. D., Melton, A. C., et al. (2009) · Journal of Clinical Investigation · doi:10.1172/jci40053 · Cited by 236 · see citing works
Scraping fibrosis: Expressway to the core of fibrosis
Mehal, W. Z., Iredale, J. P., & Friedman, S. L. (2011) · Nature Medicine · doi:10.1038/nm0511-552 · Cited by 204 · see citing works
TH-17: a giant step from TH1 and TH2
Wynn, T. A. (2005) · Nature Immunology · doi:10.1038/ni1105-1069 · Cited by 162 · see citing works
Yoshizaki, A., Yanaba, K., Iwata, Y., Komura, K., Ogawa, A., Akiyama, Y., Muroi, E., Hara, T., Ogawa, F., Takenaka, M., et al. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0901778 · Cited by 139 · see citing works
Pellman, J., Lyon, R. C., & Sheikh, F. (2009) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2009.09.001 · Cited by 139 · see citing works
Interleukin-17 as a drug target in human disease
Ivanov, S., & Lindén, A. (2009) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2008.11.004 · Cited by 110 · see citing works
Yang, H., Cui, B., Liu, H.-Z., Chen, Z., Yan, H., Hua, F., & Hu, Z. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.182.1.692 · Cited by 103 · see citing works
Self-citationIdiopathic Retroperitoneal Fibrosis: A Review of the Pathogenesis and Approaches to Treatment
Swartz, R. D. (2009) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2009.04.019 · Cited by 90 · see citing works
Knapp, S., Florquin, S., Golenbock, D. T., & van der Poll, T. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.5.3189 · Cited by 84 · see citing works
IFN-γ Regulates the Requirement for IL-17 in Proteoglycan-Induced Arthritis
Doodes, P. D., Cao, Y., Hamel, K. M., Wang, Y., Rodeghero, R., Mikecz, K., Glant, T. T., Iwakura, Y., & Finnegan, A. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0902907 · Cited by 75 · see citing works
Liu, Y.-Y., Cai, W., Yang, H.-Z., Cui, B., Chen, Z.-R., Liu, H.-Z., Yan, J., Jin, W., Yan, H.-M., Xin, B.-M., et al. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.11.7349 · Cited by 50 · see citing works
Self-citationAITKEN, K. J., Tölg, C., Panchal, T., Leslie, B., Yu, J., Elkelini, M. S., Sabha, N., Tse, D., Lorenzo, A. J., HASSOUNA, M. M., et al. (2009) · American Journal Of Pathology · doi:10.2353/ajpath.2010.080834 · Cited by 49 · see citing works
Mediatory molecules that fuse autophagosomes and lysosomes
Furuta, N., Yoshimori, T., & Amano, A. (2010) · Autophagy · doi:10.4161/auto.6.3.11418 · Cited by 14 · see citing works
Buckley, S., Medina, C., & Ehrhardt, C. (2009) · doi:10.1164/ajrccm-conference.2009.179.1_meetingabstracts.a5298 · Cited by 1 · see citing works
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Klionsky, D. J., Abdel-Aziz, A. K., Abdelfatah, S., Abdellatif, M., Abdoli, A., Abel, S., Abeliovich, H., Abildgaard, M. H., Abudu, Y. P., Acevedo-Arozena, A., et al. (2021) · Autophagy · doi:10.1080/15548627.2020.1797280 · Cited by 2,622 · see citing works
Self-citationTargeting IL-17 and TH17 cells in chronic inflammation
Miossec, P., & Kolls, J. K. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3794 · Cited by 1,414 · see citing works
Resolution of inflammation: a new therapeutic frontier
Fullerton, J. N., & Gilroy, D. W. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.39 · Cited by 937 · see citing works
Autophagy and inflammation in chronic respiratory disease
Racanelli, A. C., Kikkers, S. A., Choi, A. M. K., & Cloonan, S. M. (2018) · Autophagy · doi:10.1080/15548627.2017.1389823 · Cited by 547 · see citing works
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Larson-Casey, J. L., Deshane, J. S., Ryan, A. J., Thannickal, V. J., & Carter, A. B. (2016) · Immunity · doi:10.1016/j.immuni.2016.01.001 · Cited by 428 · see citing works
Immune mechanisms in pulmonary fibrosis
Kolahian, S., Fernandez, I. E., Eickelberg, O., & Hartl, D. (2016) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2016-0121tr · Cited by 349 · see citing works
The Role of Immune and Inflammatory Cells in Idiopathic Pulmonary Fibrosis
Desai, O., Winkler, J., Minasyan, M., & Herzog, E. L. (2018) · Frontiers in Medicine · doi:10.3389/fmed.2018.00043 · Cited by 314 · see citing works
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Faust, H. J., Zhang, H., Han, J., Wolf, M. T., Jeon, O. H., Sadtler, K., Peña, A. N., Chung, L., Maestas, D. R., Tam, A. J., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci134091 · Cited by 260 · see citing works
Zhang, X.-W., Zhou, J.-C., Peng, D., Hua, F., Li, K., Yu, J.-J., Lv, X.-X., Cui, B., Liu, S.-S., Yu, J.-M., et al. (2020) · Autophagy · doi:10.1080/15548627.2019.1635383 · Cited by 166 · see citing works
Self-citationEssential role for the ATG4B protease and autophagy in bleomycin-induced pulmonary fibrosis
Cabrera, S., Maciel, M., Herrera, I., Nava, T., Vergara, F., Gaxiola, M., López-Otín, C., Selman, M., & Pardo, A. (2015) · Autophagy · doi:10.1080/15548627.2015.1034409 · Cited by 163 · see citing works
Yang, H.-Z., Wang, J.-P., Mi, S., Liu, H.-Z., Cui, B., Yan, H.-M., Yan, J., Li, Z., Liu, H., Hua, F., et al. (2012) · The American Journal of Pathology · doi:10.1016/j.ajpath.2011.09.019 · Cited by 155 · see citing works
Self-citationAutophagy, an important therapeutic target for pulmonary fibrosis diseases
Zhao, H., Wang, Y., Qiu, T., Liu, W., & Yao, P. (2020) · Clinica Chimica Acta · doi:10.1016/j.cca.2019.12.016 · Cited by 115 · see citing works
B cell activating factor is central to bleomycin- and IL-17-mediated experimental pulmonary fibrosis
François, A., Gombault, A., Villeret, B., Alsaleh, G., Fanny, M., Gasse, P., Adam, S. M., Crestani, B., Sibilia, J., Schneider, P., et al. (2015) · Journal of Autoimmunity · doi:10.1016/j.jaut.2014.08.003 · Cited by 109 · see citing works
Park, M.-J., Moon, S.-J., Lee, E.-J., Jung, K.-A., Kim, E.-K., Kim, D.-S., Lee, J.-H., Kwok, S.-K., Min, J.-K., Park, S.-H., et al. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01611 · Cited by 89 · see citing works
Autophagy in Pulmonary Diseases
Nakahira, K., Pabon Porras, M. A., & Choi, A. M. K. (2016) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201512-2468so · Cited by 78 · see citing works
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Abdel Fattah, E., Bhattacharya, A., Herron, A., Safdar, Z., & Eissa, N. T. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1402277 · Cited by 77 · see citing works
Chen, Y., Li, C., Weng, D., Song, L., Tang, W., Dai, W., Yu, Y., Liu, F., Zhao, M., Lu, C., et al. (2014) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2013.11.012 · Cited by 75 · see citing works
Mohamed, D. I., Khairy, E., Tawfek, S. S., Habib, E. K., & Fetouh, M. A. (2019) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.10.133 · Cited by 62 · see citing works
Zhang, X.-W., Mi, S., Li, Z., Zhou, J.-C., Xie, J., Hua, F., Li, K., Cui, B., Lv, X.-X., Yu, J.-J., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.14266 · Cited by 48 · see citing works
Self-citationDong, Z., Lu, X., Yang, Y., Zhang, T., Li, Y., Chai, Y., Lei, W., Li, C., Ai, L., & Tai, W. (2015) · BMC Pulmonary Medicine · doi:10.1186/s12890-015-0012-4 · Cited by 42 · see citing works
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Wang, B.-Z., Wang, L.-P., Han, H., Cao, F.-L., Li, G.-Y., Xu, J.-L., Wang, X.-W., & Wang, L.-X. (2014) · Experimental Lung Research · doi:10.3109/01902148.2013.872210 · Cited by 33 · see citing works
Self-citationHuang, Q., Chu, S., Yin, X., Yu, X., Kang, C., Li, X., & Qiu, Y. (2016) · The Tohoku Journal of Experimental Medicine · doi:10.1620/tjem.240.269 · Cited by 29 · see citing works
- Authors
- Mi, S., Li, Z., Yang, H.-Z., Liu, H., Wang, J.-P., Ma, Y.-G., Wang, X.-X., Liu, H.-Z., Sun, W., & Hu, Z.-W.
- Affiliations
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Molecular Immunology and Pharmacology Laboratory, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100050 ,
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-09
- Volume
- 187
- Issue
- 6
- Pages
- 3003-3014
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2112119237
- Cited by
- 370
- References
- 38
- Citations by year
- 2026: 17 · 2025: 19 · 2024: 18 · 2023: 28 · 2022: 26 · 2021: 33 · 2020: 35 · 2019: 24 · 2018: 24 · 2017: 30 · 2016: 32 · 2015: 25 · 2014: 21 · 2013: 19 · 2012: 16
- FWCI
- 16.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Keywords
- IL-17A, pulmonary fibrosis, TGF-β1, collagen synthesis, epithelial-mesenchymal transition, alveolar epithelial cells, bleomycin-induced lung injury, silica-induced lung injury, autophagy, autophagic cell death, Th1 response
- MeSH terms
- Animals, Autophagy, Bronchoalveolar Lavage Fluid, Cell Separation, Collagen, Flow Cytometry, Male, Mice, Inbred C57BL, Pneumonia, Pulmonary Fibrosis, Blotting, Western, Signal Transduction, Microscopy, Confocal, Reverse Transcriptase Polymerase Chain Reaction, Interleukin-17, Mice, Transforming Growth Factor beta1, Epithelial-Mesenchymal Transition
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