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 un...
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MDPI AG
2023-07-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/14/1899 |
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| author | Simon Ebert Lan Zang Noor Ismail Michael Otabil Adrian Fröhlich Virginia Egea Susann Ács Mikkel Hoeberg Marie-Luise Berres Christian Weber José M. A. Moreira Christian Ries Jürgen Bernhagen Omar El Bounkari |
| author_facet | Simon Ebert Lan Zang Noor Ismail Michael Otabil Adrian Fröhlich Virginia Egea Susann Ács Mikkel Hoeberg Marie-Luise Berres Christian Weber José M. A. Moreira Christian Ries Jürgen Bernhagen Omar El Bounkari |
| author_sort | Simon Ebert |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T01:11:44Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T01:11:44Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-7f4b293c46944de99806238b9e5052192023-11-18T18:46:46ZengMDPI AGCells2073-44092023-07-011214189910.3390/cells12141899Tissue Inhibitor of Metalloproteinases-1 Interacts with CD74 to Promote AKT Signaling, Monocyte Recruitment Responses, and Vascular Smooth Muscle Cell ProliferationSimon Ebert0Lan Zang1Noor Ismail2Michael Otabil3Adrian Fröhlich4Virginia Egea5Susann Ács6Mikkel Hoeberg7Marie-Luise Berres8Christian Weber9José M. A. Moreira10Christian Ries11Jürgen Bernhagen12Omar El Bounkari13Department of Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilian-University (LMU) Munich, 81377 Munich, GermanyInstitute for Cardiovascular Prevention (IPEK), Klinikum der Universität München, Ludwig-Maximilian-University (LMU) Munich, 80336 Munich, GermanyDepartment of Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilian-University (LMU) Munich, 81377 Munich, GermanyDepartment of Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilian-University (LMU) Munich, 81377 Munich, GermanyDepartment of Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilian-University (LMU) Munich, 81377 Munich, GermanyInstitute for Cardiovascular Prevention (IPEK), Klinikum der Universität München, Ludwig-Maximilian-University (LMU) Munich, 80336 Munich, GermanyInstitute for Cardiovascular Prevention (IPEK), Klinikum der Universität München, Ludwig-Maximilian-University (LMU) Munich, 80336 Munich, GermanyDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, DenmarkDepartment of Internal Medicine III, RWTH Aachen University, 52074 Aachen, GermanyInstitute for Cardiovascular Prevention (IPEK), Klinikum der Universität München, Ludwig-Maximilian-University (LMU) Munich, 80336 Munich, GermanyDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, DenmarkInstitute for Cardiovascular Prevention (IPEK), Klinikum der Universität München, Ludwig-Maximilian-University (LMU) Munich, 80336 Munich, GermanyDepartment of Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilian-University (LMU) Munich, 81377 Munich, GermanyDepartment of Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilian-University (LMU) Munich, 81377 Munich, GermanyTissue 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.https://www.mdpi.com/2073-4409/12/14/1899cytokinechemokinecell migration/adhesionproliferationvascular inflammationatherogenesis |
| spellingShingle | Simon Ebert Lan Zang Noor Ismail Michael Otabil Adrian Fröhlich Virginia Egea Susann Ács Mikkel Hoeberg Marie-Luise Berres Christian Weber José M. A. Moreira Christian Ries Jürgen Bernhagen Omar El Bounkari Tissue Inhibitor of Metalloproteinases-1 Interacts with CD74 to Promote AKT Signaling, Monocyte Recruitment Responses, and Vascular Smooth Muscle Cell Proliferation Cells cytokine chemokine cell migration/adhesion proliferation vascular inflammation atherogenesis |
| title | Tissue Inhibitor of Metalloproteinases-1 Interacts with CD74 to Promote AKT Signaling, Monocyte Recruitment Responses, and Vascular Smooth Muscle Cell Proliferation |
| title_full | Tissue Inhibitor of Metalloproteinases-1 Interacts with CD74 to Promote AKT Signaling, Monocyte Recruitment Responses, and Vascular Smooth Muscle Cell Proliferation |
| title_fullStr | Tissue Inhibitor of Metalloproteinases-1 Interacts with CD74 to Promote AKT Signaling, Monocyte Recruitment Responses, and Vascular Smooth Muscle Cell Proliferation |
| title_full_unstemmed | Tissue Inhibitor of Metalloproteinases-1 Interacts with CD74 to Promote AKT Signaling, Monocyte Recruitment Responses, and Vascular Smooth Muscle Cell Proliferation |
| title_short | Tissue Inhibitor of Metalloproteinases-1 Interacts with CD74 to Promote AKT Signaling, Monocyte Recruitment Responses, and Vascular Smooth Muscle Cell Proliferation |
| title_sort | tissue inhibitor of metalloproteinases 1 interacts with cd74 to promote akt signaling monocyte recruitment responses and vascular smooth muscle cell proliferation |
| topic | cytokine chemokine cell migration/adhesion proliferation vascular inflammation atherogenesis |
| url | https://www.mdpi.com/2073-4409/12/14/1899 |
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