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.
TIMP-1 is a novel ligand of Amyloid Precursor Protein and triggers a proinflammatory phenotype in human monocytes
Disclosures: The authors declare no competing interests exist.
- Award Id(s): KR2047/1-3,KR2047/8-1,KR2047/15-1,424926990,442405234,329628492 – SFB 1321
- Award Id(s): TI07.001
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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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