Efferocytosis fuels malignant pleural effusion through TIMP1

Abstract

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.

Bibliografische Daten

OriginalspracheEnglisch
Aufsatznummereabd6734
ISSN2375-2548
DOIs
StatusVeröffentlicht - 08.2021

Anmerkungen des Dekanats

Funding Information:
This work was supported by the Deutsche Forschungsgemeinschaft (grant GA 2441/3-1 to N.G., grant HU 1714/10-1 to S.H., and grant SFB841 to L.B.), the European Research Council (StG 715271 to N.G. and CoG 865466 to S.H.), Ernst Jung-Stiftung Hamburg (to S.H.), Stiftung Experimentelle Biomedizin (to S.H.), European Respiratory Society/short-term fellowship (to A.D.G.), Else Kr?ner Memorial Stipendium (to A.D.G.), Werner Otto Stiftung (to A.D.G. and L.B.), ?Close the gap? funding of UKE (to L.B.), Erich und Gertrud Roggenbuck Stiftung (to A.D.G.), Hamburger Krebsgesellschaft Stiftung (to A.D.G.), and German Centre for Cardiovascular Research (DZHK) (FKZ 81Z0710108) (to D.L.). S.H. has an endowed Heisenberg Professorship awarded by the Deutsche

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