Tissue Inhibitor of Metalloproteinases-1 Interacts with CD74 to Promote AKT Signaling, Monocyte Recruitment Responses, and Vascular Smooth Muscle Cell Proliferation
Tissue inhibitor of metalloproteinases-1 (TIMP-1), an important regulator of matrix metalloproteinases (MMPs), has recently been shown to interact with CD74, a receptor for macrophage migration inhibitory factor (MIF). However, the biological effects mediated by TIMP-1 through CD74 remain largely unexplored. Using sequence alignment and in silico protein-protein docking analysis, we demonstrated that TIMP-1 shares residues with both MIF and MIF-2, crucial for CD74 binding, but not for CXCR4. Subcellular colocalization, immunoprecipitation, and internalization experiments supported these findings, demonstrating that TIMP-1 interacts with surface-expressed CD74, resulting in its internalization in a dose-dependent manner, as well as with a soluble CD74 ectodomain fragment (sCD74). This prompted us to study the effects of the TIMP-1-CD74 axis on monocytes and vascular smooth muscle cells (VSCMs) to assess its impact on vascular inflammation. A phospho-kinase array revealed the activation of serine/threonine kinases by TIMP-1 in THP-1 pre-monocytes, in particular AKT. Similarly, TIMP-1 dose-dependently triggered the phosphorylation of AKT and ERK1/2 in primary human monocytes. Importantly, Transwell migration, 3D-based Chemotaxis, and flow adhesion assays demonstrated that TIMP-1 engagement of CD74 strongly promotes the recruitment response of primary human monocytes, while live cell imaging studies revealed a profound activating effect on VSMC proliferation. Finally, re-analysis of scRNA-seq data highlighted the expression patterns of TIMP-1 and CD74 in human atherosclerotic lesions, thus, together with our experimental data, indicating a role for the TIMP-1-CD74 axis in vascular inflammation and atherosclerosis.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
Cells - 12(2023), 14 vom: 20. Juli |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ebert, Simon [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 31.07.2023 Date Revised 31.07.2023 published: Electronic Citation Status MEDLINE |
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| doi: |
10.3390/cells12141899 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM360084354 |
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| 245 | 1 | 0 | |a Tissue Inhibitor of Metalloproteinases-1 Interacts with CD74 to Promote AKT Signaling, Monocyte Recruitment Responses, and Vascular Smooth Muscle Cell Proliferation |
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| 500 | |a Date Revised 31.07.2023 | ||
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Tissue inhibitor of metalloproteinases-1 (TIMP-1), an important regulator of matrix metalloproteinases (MMPs), has recently been shown to interact with CD74, a receptor for macrophage migration inhibitory factor (MIF). However, the biological effects mediated by TIMP-1 through CD74 remain largely unexplored. Using sequence alignment and in silico protein-protein docking analysis, we demonstrated that TIMP-1 shares residues with both MIF and MIF-2, crucial for CD74 binding, but not for CXCR4. Subcellular colocalization, immunoprecipitation, and internalization experiments supported these findings, demonstrating that TIMP-1 interacts with surface-expressed CD74, resulting in its internalization in a dose-dependent manner, as well as with a soluble CD74 ectodomain fragment (sCD74). This prompted us to study the effects of the TIMP-1-CD74 axis on monocytes and vascular smooth muscle cells (VSCMs) to assess its impact on vascular inflammation. A phospho-kinase array revealed the activation of serine/threonine kinases by TIMP-1 in THP-1 pre-monocytes, in particular AKT. Similarly, TIMP-1 dose-dependently triggered the phosphorylation of AKT and ERK1/2 in primary human monocytes. Importantly, Transwell migration, 3D-based Chemotaxis, and flow adhesion assays demonstrated that TIMP-1 engagement of CD74 strongly promotes the recruitment response of primary human monocytes, while live cell imaging studies revealed a profound activating effect on VSMC proliferation. Finally, re-analysis of scRNA-seq data highlighted the expression patterns of TIMP-1 and CD74 in human atherosclerotic lesions, thus, together with our experimental data, indicating a role for the TIMP-1-CD74 axis in vascular inflammation and atherosclerosis | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Zang, Lan |e verfasserin |4 aut | |
| 700 | 1 | |a Ismail, Noor |e verfasserin |4 aut | |
| 700 | 1 | |a Otabil, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Fröhlich, Adrian |e verfasserin |4 aut | |
| 700 | 1 | |a Egea, Virginia |e verfasserin |4 aut | |
| 700 | 1 | |a Ács, Susann |e verfasserin |4 aut | |
| 700 | 1 | |a Hoeberg, Mikkel |e verfasserin |4 aut | |
| 700 | 1 | |a Berres, Marie-Luise |e verfasserin |4 aut | |
| 700 | 1 | |a Weber, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a Moreira, José M A |e verfasserin |4 aut | |
| 700 | 1 | |a Ries, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a Bernhagen, Jürgen |e verfasserin |4 aut | |
| 700 | 1 | |a El Bounkari, Omar |e verfasserin |4 aut | |
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