Reprogramming alveolar macrophage responses to TGF-β reveals CCR2(+) monocyte activity that promotes bronchiolitis obliterans syndrome
Bronchiolitis obliterans syndrome (BOS) is a major impediment to lung transplant survival and is generally resistant to medical therapy. Extracorporeal photophoresis (ECP) is an immunomodulatory therapy that shows promise in stabilizing BOS patients, but its mechanisms of action are unclear. In a mo...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Society for Clinical Investigation
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9525120/ https://www.ncbi.nlm.nih.gov/pubmed/36189800 http://dx.doi.org/10.1172/JCI159229 |
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author | Liu, Zhiyi Liao, Fuyi Zhu, Jihong Zhou, Dequan Heo, Gyu Seong Leuhmann, Hannah P. Scozzi, Davide Parks, Antanisha Hachem, Ramsey Byers, Derek E. Tague, Laneshia K. Kulkarni, Hrishikesh S. Cano, Marlene Wong, Brian W. Li, Wenjun Huang, Howard J. Krupnick, Alexander S. Kreisel, Daniel Liu, Yongjian Gelman, Andrew E. |
author_facet | Liu, Zhiyi Liao, Fuyi Zhu, Jihong Zhou, Dequan Heo, Gyu Seong Leuhmann, Hannah P. Scozzi, Davide Parks, Antanisha Hachem, Ramsey Byers, Derek E. Tague, Laneshia K. Kulkarni, Hrishikesh S. Cano, Marlene Wong, Brian W. Li, Wenjun Huang, Howard J. Krupnick, Alexander S. Kreisel, Daniel Liu, Yongjian Gelman, Andrew E. |
author_sort | Liu, Zhiyi |
collection | PubMed |
description | Bronchiolitis obliterans syndrome (BOS) is a major impediment to lung transplant survival and is generally resistant to medical therapy. Extracorporeal photophoresis (ECP) is an immunomodulatory therapy that shows promise in stabilizing BOS patients, but its mechanisms of action are unclear. In a mouse lung transplant model, we show that ECP blunts alloimmune responses and inhibits BOS through lowering airway TGF-β bioavailability without altering its expression. Surprisingly, ECP-treated leukocytes were primarily engulfed by alveolar macrophages (AMs), which were reprogrammed to become less responsive to TGF-β and reduce TGF-β bioavailability through secretion of the TGF-β antagonist decorin. In untreated recipients, high airway TGF-β activity stimulated AMs to express CCL2, leading to CCR2(+) monocyte-driven BOS development. Moreover, we found TGF-β receptor 2–dependent differentiation of CCR2(+) monocytes was required for the generation of monocyte-derived AMs, which in turn promoted BOS by expanding tissue-resident memory CD8(+) T cells that inflicted airway injury through Blimp-1–mediated granzyme B expression. Thus, through studying the effects of ECP, we have identified an AM functional plasticity that controls a TGF-β–dependent network that couples CCR2(+) monocyte recruitment and differentiation to alloimmunity and BOS. |
format | Online Article Text |
id | pubmed-9525120 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-95251202022-10-05 Reprogramming alveolar macrophage responses to TGF-β reveals CCR2(+) monocyte activity that promotes bronchiolitis obliterans syndrome Liu, Zhiyi Liao, Fuyi Zhu, Jihong Zhou, Dequan Heo, Gyu Seong Leuhmann, Hannah P. Scozzi, Davide Parks, Antanisha Hachem, Ramsey Byers, Derek E. Tague, Laneshia K. Kulkarni, Hrishikesh S. Cano, Marlene Wong, Brian W. Li, Wenjun Huang, Howard J. Krupnick, Alexander S. Kreisel, Daniel Liu, Yongjian Gelman, Andrew E. J Clin Invest Research Article Bronchiolitis obliterans syndrome (BOS) is a major impediment to lung transplant survival and is generally resistant to medical therapy. Extracorporeal photophoresis (ECP) is an immunomodulatory therapy that shows promise in stabilizing BOS patients, but its mechanisms of action are unclear. In a mouse lung transplant model, we show that ECP blunts alloimmune responses and inhibits BOS through lowering airway TGF-β bioavailability without altering its expression. Surprisingly, ECP-treated leukocytes were primarily engulfed by alveolar macrophages (AMs), which were reprogrammed to become less responsive to TGF-β and reduce TGF-β bioavailability through secretion of the TGF-β antagonist decorin. In untreated recipients, high airway TGF-β activity stimulated AMs to express CCL2, leading to CCR2(+) monocyte-driven BOS development. Moreover, we found TGF-β receptor 2–dependent differentiation of CCR2(+) monocytes was required for the generation of monocyte-derived AMs, which in turn promoted BOS by expanding tissue-resident memory CD8(+) T cells that inflicted airway injury through Blimp-1–mediated granzyme B expression. Thus, through studying the effects of ECP, we have identified an AM functional plasticity that controls a TGF-β–dependent network that couples CCR2(+) monocyte recruitment and differentiation to alloimmunity and BOS. American Society for Clinical Investigation 2022-10-03 /pmc/articles/PMC9525120/ /pubmed/36189800 http://dx.doi.org/10.1172/JCI159229 Text en © 2022 Liu et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Liu, Zhiyi Liao, Fuyi Zhu, Jihong Zhou, Dequan Heo, Gyu Seong Leuhmann, Hannah P. Scozzi, Davide Parks, Antanisha Hachem, Ramsey Byers, Derek E. Tague, Laneshia K. Kulkarni, Hrishikesh S. Cano, Marlene Wong, Brian W. Li, Wenjun Huang, Howard J. Krupnick, Alexander S. Kreisel, Daniel Liu, Yongjian Gelman, Andrew E. Reprogramming alveolar macrophage responses to TGF-β reveals CCR2(+) monocyte activity that promotes bronchiolitis obliterans syndrome |
title | Reprogramming alveolar macrophage responses to TGF-β reveals CCR2(+) monocyte activity that promotes bronchiolitis obliterans syndrome |
title_full | Reprogramming alveolar macrophage responses to TGF-β reveals CCR2(+) monocyte activity that promotes bronchiolitis obliterans syndrome |
title_fullStr | Reprogramming alveolar macrophage responses to TGF-β reveals CCR2(+) monocyte activity that promotes bronchiolitis obliterans syndrome |
title_full_unstemmed | Reprogramming alveolar macrophage responses to TGF-β reveals CCR2(+) monocyte activity that promotes bronchiolitis obliterans syndrome |
title_short | Reprogramming alveolar macrophage responses to TGF-β reveals CCR2(+) monocyte activity that promotes bronchiolitis obliterans syndrome |
title_sort | reprogramming alveolar macrophage responses to tgf-β reveals ccr2(+) monocyte activity that promotes bronchiolitis obliterans syndrome |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9525120/ https://www.ncbi.nlm.nih.gov/pubmed/36189800 http://dx.doi.org/10.1172/JCI159229 |
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