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Efferocytosis fuels malignant pleural effusion through TIMP1

Malignant pleural effusion (MPE) results from the capacity of several human cancers to metastasize to the pleural cavity. No effective treatments are currently available, reflecting our insufficient understanding of the basic mechanisms leading to MPE progression. Here, we found that efferocytosis t...

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Main Authors: Zhao, Lilan (Author) , Giannou, Anastasios D. (Author) , Xu, Yang (Author) , Shiri, Ahmad Mustafa (Author) , Liebold, Imke (Author) , Steglich, Babett (Author) , Bedke, Tanja (Author) , Zhang, Tao (Author) , Lücke, Jöran (Author) , Scognamiglio, Pasquale (Author) , Kempski, Jan (Author) , Woestemeier, Anna (Author) , Chen, Jing (Author) , Agalioti, Theodora (Author) , Zazara, Dimitra E. (Author) , Lindner, Diana (Author) , Janning, Melanie (Author) , Hennigs, Jan K. (Author) , Jagirdar, Rajesh M. (Author) , Kotsiou, Ourania S. (Author) , Zarogiannis, Sotirios G. (Author) , Kobayashi, Yasushi (Author) , Izbicki, Jacob R. (Author) , Ghosh, Sourav (Author) , Rothlin, Carla V. (Author) , Bosurgi, Lidia (Author) , Huber, Samuel (Author) , Gagliani, Nicola (Author)
Format: Article (Journal)
Language:English
Published: 13 Aug 2021
In: Science advances
Year: 2021, Volume: 7, Issue: 33, Pages: 1-16
ISSN:2375-2548
DOI:10.1126/sciadv.abd6734
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1126/sciadv.abd6734
Verlag, lizenzpflichtig, Volltext: https://www.science.org/doi/10.1126/sciadv.abd6734
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Author Notes:Lilan Zhao, Anastasios D. Giannou, Yang Xu, Ahmad Mustafa Shiri, Imke Liebold, Babett Steglich, Tanja Bedke, Tao Zhang, Jöran Lücke, Pasquale Scognamiglio, Jan Kempski, Anna Woestemeier, Jing Chen, Theodora Agalioti, Dimitra E. Zazara, Diana Lindner, Melanie Janning, Jan K. Hennigs, Rajesh M. Jagirdar, Ourania S. Kotsiou, Sotirios G. Zarogiannis, Yasushi Kobayashi, Jacob R. Izbicki, Sourav Ghosh, Carla V. Rothlin, Lidia Bosurgi, Samuel Huber, Nicola Gagliani

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520 |a Malignant pleural effusion (MPE) results from the capacity of several human cancers to metastasize to the pleural cavity. No effective treatments are currently available, reflecting our insufficient understanding of the basic mechanisms leading to MPE progression. Here, we found that efferocytosis through the receptor tyrosine kinases AXL and MERTK led to the production of interleukin-10 (IL-10) by four distinct pleural cavity macrophage (Mφ) subpopulations characterized by different metabolic states and cell chemotaxis properties. In turn, IL-10 acts on dendritic cells (DCs) inducing the production of tissue inhibitor of metalloproteinases 1 (TIMP1). Genetic ablation of Axl and Mertk in Mφs or IL-10 receptor in DCs or Timp1 substantially reduced MPE progression. Our results delineate an inflammatory cascade—from the clearance of apoptotic cells by Mφs, to production of IL-10, to induction of TIMP1 in DCs—that facilitates MPE progression. This inflammatory cascade offers a series of therapeutic targets for MPE. 
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