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TIMP-1 is a novel ligand of Amyloid Precursor Protein and triggers a proinflammatory phenotype in human monocytes

The emerging cytokine tissue inhibitor of metalloproteinases-1 (TIMP-1) correlates with the progression of inflammatory diseases, including cancer. However, the effects of TIMP-1 on immune cell activation and underlying molecular mechanisms are largely unknown. Unbiased ligand-receptor-capture-scree...

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Autores principales: Eckfeld, Celina, Schoeps, Benjamin, Häußler, Daniel, Frädrich, Julian, Bayerl, Felix, Böttcher, Jan Philipp, Knolle, Percy, Heisz, Simone, Prokopchuk, Olga, Hauner, Hans, Munkhbaatar, Enkhtsetseg, Demir, Ihsan Ekin, Hermann, Chris D., Krüger, Achim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9837626/
https://www.ncbi.nlm.nih.gov/pubmed/36629908
http://dx.doi.org/10.1083/jcb.202206095
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author Eckfeld, Celina
Schoeps, Benjamin
Häußler, Daniel
Frädrich, Julian
Bayerl, Felix
Böttcher, Jan Philipp
Knolle, Percy
Heisz, Simone
Prokopchuk, Olga
Hauner, Hans
Munkhbaatar, Enkhtsetseg
Demir, Ihsan Ekin
Hermann, Chris D.
Krüger, Achim
author_facet Eckfeld, Celina
Schoeps, Benjamin
Häußler, Daniel
Frädrich, Julian
Bayerl, Felix
Böttcher, Jan Philipp
Knolle, Percy
Heisz, Simone
Prokopchuk, Olga
Hauner, Hans
Munkhbaatar, Enkhtsetseg
Demir, Ihsan Ekin
Hermann, Chris D.
Krüger, Achim
author_sort Eckfeld, Celina
collection PubMed
description The emerging cytokine tissue inhibitor of metalloproteinases-1 (TIMP-1) correlates with the progression of inflammatory diseases, including cancer. However, the effects of TIMP-1 on immune cell activation and underlying molecular mechanisms are largely unknown. Unbiased ligand-receptor-capture-screening revealed TIMP-1-interaction with Amyloid Precursor Protein (APP) family members, namely APP and Amyloid Precursor-like Protein-2 (APLP2), which was confirmed by pull-down assays and confocal microscopy. We found that TIMP-1 triggered glucose uptake and proinflammatory cytokine expression in human monocytes. In cancer patients, TIMP-1 expression positively correlated with proinflammatory cytokine expression and processes associated with monocyte activation. In pancreatic cancer, TIMP-1 plasma levels correlated with the monocyte activation marker sCD163, and the combined use of both clinically accessible plasma proteins served as a powerful prognostic indicator. Mechanistically, TIMP-1 triggered monocyte activation by its C-terminal domain and via APP as demonstrated by in vitro interference, in silico docking, and the employment of recombinant TIMP-1 variants. Identification of TIMP-1 as a trigger of monocyte activation opens new therapeutic perspectives for inflammatory diseases.
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spelling pubmed-98376262023-07-11 TIMP-1 is a novel ligand of Amyloid Precursor Protein and triggers a proinflammatory phenotype in human monocytes Eckfeld, Celina Schoeps, Benjamin Häußler, Daniel Frädrich, Julian Bayerl, Felix Böttcher, Jan Philipp Knolle, Percy Heisz, Simone Prokopchuk, Olga Hauner, Hans Munkhbaatar, Enkhtsetseg Demir, Ihsan Ekin Hermann, Chris D. Krüger, Achim J Cell Biol Article The emerging cytokine tissue inhibitor of metalloproteinases-1 (TIMP-1) correlates with the progression of inflammatory diseases, including cancer. However, the effects of TIMP-1 on immune cell activation and underlying molecular mechanisms are largely unknown. Unbiased ligand-receptor-capture-screening revealed TIMP-1-interaction with Amyloid Precursor Protein (APP) family members, namely APP and Amyloid Precursor-like Protein-2 (APLP2), which was confirmed by pull-down assays and confocal microscopy. We found that TIMP-1 triggered glucose uptake and proinflammatory cytokine expression in human monocytes. In cancer patients, TIMP-1 expression positively correlated with proinflammatory cytokine expression and processes associated with monocyte activation. In pancreatic cancer, TIMP-1 plasma levels correlated with the monocyte activation marker sCD163, and the combined use of both clinically accessible plasma proteins served as a powerful prognostic indicator. Mechanistically, TIMP-1 triggered monocyte activation by its C-terminal domain and via APP as demonstrated by in vitro interference, in silico docking, and the employment of recombinant TIMP-1 variants. Identification of TIMP-1 as a trigger of monocyte activation opens new therapeutic perspectives for inflammatory diseases. Rockefeller University Press 2023-01-11 /pmc/articles/PMC9837626/ /pubmed/36629908 http://dx.doi.org/10.1083/jcb.202206095 Text en © 2023 Eckfeld et al. https://creativecommons.org/licenses/by-nc-sa/4.0/http://www.rupress.org/terms/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Eckfeld, Celina
Schoeps, Benjamin
Häußler, Daniel
Frädrich, Julian
Bayerl, Felix
Böttcher, Jan Philipp
Knolle, Percy
Heisz, Simone
Prokopchuk, Olga
Hauner, Hans
Munkhbaatar, Enkhtsetseg
Demir, Ihsan Ekin
Hermann, Chris D.
Krüger, Achim
TIMP-1 is a novel ligand of Amyloid Precursor Protein and triggers a proinflammatory phenotype in human monocytes
title TIMP-1 is a novel ligand of Amyloid Precursor Protein and triggers a proinflammatory phenotype in human monocytes
title_full TIMP-1 is a novel ligand of Amyloid Precursor Protein and triggers a proinflammatory phenotype in human monocytes
title_fullStr TIMP-1 is a novel ligand of Amyloid Precursor Protein and triggers a proinflammatory phenotype in human monocytes
title_full_unstemmed TIMP-1 is a novel ligand of Amyloid Precursor Protein and triggers a proinflammatory phenotype in human monocytes
title_short TIMP-1 is a novel ligand of Amyloid Precursor Protein and triggers a proinflammatory phenotype in human monocytes
title_sort timp-1 is a novel ligand of amyloid precursor protein and triggers a proinflammatory phenotype in human monocytes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9837626/
https://www.ncbi.nlm.nih.gov/pubmed/36629908
http://dx.doi.org/10.1083/jcb.202206095
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