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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January 11 2023
TIMP-1 is a novel ligand of Amyloid Precursor Protein and triggers a proinflammatory phenotype in human monocytes
Celina Eckfeld
,
Celina Eckfeld
(Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review & editing)
1
School of Medicine, Institute of Experimental Oncology and Therapy Research, Technical University of Munich
, Munich, Germany
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Benjamin Schoeps
,
Benjamin Schoeps
(Formal analysis, Investigation, Methodology, Writing - review & editing)
1
School of Medicine, Institute of Experimental Oncology and Therapy Research, Technical University of Munich
, Munich, Germany
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Daniel Häußler
,
Daniel Häußler
(Formal analysis, Investigation, Methodology, Validation, Writing - review & editing)
1
School of Medicine, Institute of Experimental Oncology and Therapy Research, Technical University of Munich
, Munich, Germany
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Julian Frädrich
,
Julian Frädrich
(Formal analysis, Investigation, Methodology, Validation, Writing - review & editing)
1
School of Medicine, Institute of Experimental Oncology and Therapy Research, Technical University of Munich
, Munich, Germany
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Felix Bayerl
,
Felix Bayerl
(Investigation, Resources, Visualization, Writing - review & editing)
2
School of Medicine, Institute of Molecular Immunology, Technical University of Munich
, Munich, Germany
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Jan Philipp Böttcher
,
Jan Philipp Böttcher
(Resources)
2
School of Medicine, Institute of Molecular Immunology, Technical University of Munich
, Munich, Germany
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Percy Knolle
,
Percy Knolle
(Conceptualization, Supervision, Writing - review & editing)
2
School of Medicine, Institute of Molecular Immunology, Technical University of Munich
, Munich, Germany
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Simone Heisz
,
Simone Heisz
(Investigation, Writing - original draft, Writing - review & editing)
3
School of Life Sciences, Else Kröner-Fresenius-Center for Nutritional Medicine, Chair of Nutritional Medicine, Technical University of Munich
, Freising-Weihenstephan, Germany
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Olga Prokopchuk
,
Olga Prokopchuk
(Investigation, Resources)
1
School of Medicine, Institute of Experimental Oncology and Therapy Research, Technical University of Munich
, Munich, Germany
4
Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich
, Munich, Germany
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Hans Hauner
,
Hans Hauner
(Writing - review & editing)
3
School of Life Sciences, Else Kröner-Fresenius-Center for Nutritional Medicine, Chair of Nutritional Medicine, Technical University of Munich
, Freising-Weihenstephan, Germany
5
School of Life Sciences, Institute for Nutritional Medicine, Technical University of Munich
, Munich, Germany
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Enkhtsetseg Munkhbaatar
,
Enkhtsetseg Munkhbaatar
(Investigation)
4
Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich
, Munich, Germany
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Ihsan Ekin Demir
,
Ihsan Ekin Demir
(Conceptualization, Supervision, Writing - review & editing)
4
Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich
, Munich, Germany
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Chris D. Hermann
,
Chris D. Hermann
(Data curation, Formal analysis, Investigation, Writing - review & editing)
1
School of Medicine, Institute of Experimental Oncology and Therapy Research, Technical University of Munich
, Munich, Germany
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Achim Krüger
(Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing)
1
School of Medicine, Institute of Experimental Oncology and Therapy Research, Technical University of Munich
, Munich, Germany
Correspondence to Achim Krüger: achim.krueger@tum.de
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Celina Eckfeld
Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review & editing
1
School of Medicine, Institute of Experimental Oncology and Therapy Research, Technical University of Munich
, Munich, Germany
Benjamin Schoeps
Formal analysis, Investigation, Methodology, Writing - review & editing
1
School of Medicine, Institute of Experimental Oncology and Therapy Research, Technical University of Munich
, Munich, Germany
Daniel Häußler
Formal analysis, Investigation, Methodology, Validation, Writing - review & editing
1
School of Medicine, Institute of Experimental Oncology and Therapy Research, Technical University of Munich
, Munich, Germany
Julian Frädrich
Formal analysis, Investigation, Methodology, Validation, Writing - review & editing
1
School of Medicine, Institute of Experimental Oncology and Therapy Research, Technical University of Munich
, Munich, Germany
Felix Bayerl
Investigation, Resources, Visualization, Writing - review & editing
2
School of Medicine, Institute of Molecular Immunology, Technical University of Munich
, Munich, Germany
Jan Philipp Böttcher
Resources
2
School of Medicine, Institute of Molecular Immunology, Technical University of Munich
, Munich, Germany
Percy Knolle
Conceptualization, Supervision, Writing - review & editing
2
School of Medicine, Institute of Molecular Immunology, Technical University of Munich
, Munich, Germany
Simone Heisz
Investigation, Writing - original draft, Writing - review & editing
3
School of Life Sciences, Else Kröner-Fresenius-Center for Nutritional Medicine, Chair of Nutritional Medicine, Technical University of Munich
, Freising-Weihenstephan, Germany
Olga Prokopchuk
Investigation, Resources
1
School of Medicine, Institute of Experimental Oncology and Therapy Research, Technical University of Munich
, Munich, Germany
4
Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich
, Munich, Germany
Hans Hauner
Writing - review & editing
3
School of Life Sciences, Else Kröner-Fresenius-Center for Nutritional Medicine, Chair of Nutritional Medicine, Technical University of Munich
, Freising-Weihenstephan, Germany
5
School of Life Sciences, Institute for Nutritional Medicine, Technical University of Munich
, Munich, Germany
Enkhtsetseg Munkhbaatar
Investigation
4
Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich
, Munich, Germany
Ihsan Ekin Demir
Conceptualization, Supervision, Writing - review & editing
4
Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich
, Munich, Germany
Chris D. Hermann
Data curation, Formal analysis, Investigation, Writing - review & editing
1
School of Medicine, Institute of Experimental Oncology and Therapy Research, Technical University of Munich
, Munich, Germany
Achim Krüger
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
School of Medicine, Institute of Experimental Oncology and Therapy Research, Technical University of Munich
, Munich, Germany
Correspondence to Achim Krüger: achim.krueger@tum.de
Disclosures: The authors declare no competing interests exist.
Received:
June 20 2022
Revision Received:
October 21 2022
Accepted:
November 28 2022
Online Issn: 1540-8140
Print Issn: 0021-9525
Funding
Funder(s):
Deutsche Forschungsgemeinschaft
- Award Id(s): KR2047/1-3,KR2047/8-1,KR2047/15-1,424926990,442405234,329628492 – SFB 1321
Funder(s):
Wilhelm-Sander-Stiftung
Funder(s):
German Center of Infection Research
- Award Id(s): TI07.001
Funder(s):
Else Kröner-Fresenius-Foundation
© 2023 Eckfeld et al.
2022
Eckfeld et al.
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/).
J Cell Biol (2023) 222 (2): e202206095.
Article history
Received:
June 20 2022
Revision Received:
October 21 2022
Accepted:
November 28 2022
Citation
Celina Eckfeld, Benjamin Schoeps, Daniel Häußler, Julian Frädrich, Felix Bayerl, Jan Philipp Böttcher, Percy Knolle, Simone Heisz, Olga Prokopchuk, Hans Hauner, Enkhtsetseg Munkhbaatar, Ihsan Ekin Demir, Chris D. Hermann, Achim Krüger; TIMP-1 is a novel ligand of Amyloid Precursor Protein and triggers a proinflammatory phenotype in human monocytes. J Cell Biol 6 February 2023; 222 (2): e202206095. doi: https://doi.org/10.1083/jcb.202206095
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