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Efferocytosis fuels malignant pleural effusion through TIMP1
Lilan Zhao1,2, Anastasios D Giannou1,3, Yang Xu1
1Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Science Advances
|August 14, 2021
Summary
Researchers identified a key inflammatory pathway driving malignant pleural effusion (MPE) progression. Blocking efferocytosis, interleukin-10 (IL-10), or tissue inhibitor of metalloproteinases 1 (TIMP1) significantly reduced MPE growth, revealing new therapeutic targets.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Malignant pleural effusion (MPE) is a common complication of various cancers.
- Current treatments for MPE are limited due to a poor understanding of its underlying mechanisms.
- Metastasis to the pleural cavity drives MPE progression.
Purpose of the Study:
- To elucidate the molecular mechanisms driving malignant pleural effusion (MPE) progression.
- To identify potential therapeutic targets for MPE treatment.
Main Methods:
- Investigated efferocytosis via AXL and MERTK in pleural cavity macrophages (Mφs).
- Assessed the role of interleukin-10 (IL-10) in dendritic cell (DC) activation.
- Analyzed the impact of TIMP1 production on MPE progression.
- Utilized genetic ablation models in mice to study the pathway.
Main Results:
- Efferocytosis by Mφs, mediated by AXL and MERTK, induced IL-10 production.
- IL-10 stimulated DCs to produce TIMP1.
- Genetic deletion of AXL/MERTK in Mφs, IL-10 receptor in DCs, or TIMP1 significantly inhibited MPE progression.
- An inflammatory cascade involving Mφs, IL-10, and DCs was identified as crucial for MPE.
Conclusions:
- A novel inflammatory cascade facilitates MPE progression, starting with efferocytosis by macrophages and leading to TIMP1 production by dendritic cells.
- Targeting this pathway, including efferocytosis receptors (AXL, MERTK), IL-10 signaling, or TIMP1, presents promising therapeutic strategies for MPE.
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