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

Abstract

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.

Diabetes increases mortality in patients with pancreatic and colorectal cancer by promoting cachexia and its associated inflammatory status

“…A) Incidence of cachexia according to Fearon et al. [ 20 ] in patients with CRC and PC, with/without diagnosed diabetes mellitus (DM). P ≤ 0.05.…”

“…Plasma IL6 levels were determined using the Human IL6 DuoSet ELISA Development System (#DY206, R&D Systems) as previously described [ 20 ].…”

Amyloid precursor protein induces reactive astrogliosis

“…It is plausible to hypothesize that such a positive feedback loop plays a role in IFN-induced remodelling of the intermediate filament network in the reactive astrocytes 93–98 . Emerging data showing that APP binds to and modifies regulators of cytokine expression 99–102 , together with reportedly blunted innate immune response observed in mice deficient in APP 103 , also suggest that consequences of the interplay between APP and the immune networks might be significantly more far-reaching than previously thought 104 .…”

Amyloid precursor protein induces reactive astrogliosis

“…54,92,93 It is therefore plausible to hypothesize that such a feedback loop plays a role in IFN-induced remodeling of the intermediate filament network in the reactive astrocytes. [94][95][96][97][98][99] Emerging data showing that APP binds to and modifies regulators of cytokine expression, [100][101][102][103] together with reportedly blunted innate immune response observed in mice deficient in APP, 104 also suggest that consequences of the interplay between APP and the immune networks might be significantly more far-reaching than previously thought. 105…”