Tissue Inhibitor of Metalloproteinases-1 Interacts with CD74 to Promote AKT Signaling, Monocyte Recruitment Responses, and Vascular Smooth Muscle Cell Proliferation

Ebert, Simon; Zang, Lan; Ismail, Noor; Otabil, Michael; Fröhlich, Adrian; Egea, Virginia; Ács, Susann; Hoeberg, Mikkel; Berres, Marie-Luise; Weber, Christian; Moreira, José M. A.; Ries, Christian; Bernhagen, Jürgen; El Bounkari, Omar

doi:10.3390/cells12141899

Open AccessArticle

Tissue Inhibitor of Metalloproteinases-1 Interacts with CD74 to Promote AKT Signaling, Monocyte Recruitment Responses, and Vascular Smooth Muscle Cell Proliferation

by

Simon Ebert

¹

,

Lan Zang

²,

Noor Ismail

¹,

Michael Otabil

¹,

Adrian Fröhlich

¹,

Virginia Egea

²

,

Susann Ács

²,

Mikkel Hoeberg

³,

Marie-Luise Berres

⁴

,

Christian Weber

^2,5,6

,

José M. A. Moreira

³

,

Christian Ries

²

,

Jürgen Bernhagen

^1,5,6,†

and

Omar El Bounkari

^1,*

¹

Department of Vascular Biology, Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilian-University (LMU) Munich, 81377 Munich, Germany

²

Institute for Cardiovascular Prevention (IPEK), Klinikum der Universität München, Ludwig-Maximilian-University (LMU) Munich, 80336 Munich, Germany

³

Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark

⁴

Department of Internal Medicine III, RWTH Aachen University, 52074 Aachen, Germany

⁵

Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany

⁶

Munich Heart Alliance, 80802 Munich, Germany

^*

Author to whom correspondence should be addressed.

^†

Senior Author.

Cells 2023, 12(14), 1899; https://doi.org/10.3390/cells12141899

Submission received: 13 June 2023 / Revised: 14 July 2023 / Accepted: 17 July 2023 / Published: 20 July 2023

(This article belongs to the Special Issue Vascular Inflammation and Atherosclerosis: From Basic Mechanisms to Therapeutic Opportunities)

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Abstract

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.

Keywords: cytokine; chemokine; cell migration/adhesion; proliferation; vascular inflammation; atherogenesis

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MDPI and ACS Style

Ebert, S.; Zang, L.; Ismail, N.; Otabil, M.; Fröhlich, A.; Egea, V.; Ács, S.; Hoeberg, M.; Berres, M.-L.; Weber, C.; et al. Tissue Inhibitor of Metalloproteinases-1 Interacts with CD74 to Promote AKT Signaling, Monocyte Recruitment Responses, and Vascular Smooth Muscle Cell Proliferation. Cells 2023, 12, 1899. https://doi.org/10.3390/cells12141899

AMA Style

Ebert S, Zang L, Ismail N, Otabil M, Fröhlich A, Egea V, Ács S, Hoeberg M, Berres M-L, Weber C, et al. Tissue Inhibitor of Metalloproteinases-1 Interacts with CD74 to Promote AKT Signaling, Monocyte Recruitment Responses, and Vascular Smooth Muscle Cell Proliferation. Cells. 2023; 12(14):1899. https://doi.org/10.3390/cells12141899

Chicago/Turabian Style

Ebert, Simon, Lan Zang, Noor Ismail, Michael Otabil, Adrian Fröhlich, Virginia Egea, Susann Ács, Mikkel Hoeberg, Marie-Luise Berres, Christian Weber, and et al. 2023. "Tissue Inhibitor of Metalloproteinases-1 Interacts with CD74 to Promote AKT Signaling, Monocyte Recruitment Responses, and Vascular Smooth Muscle Cell Proliferation" Cells 12, no. 14: 1899. https://doi.org/10.3390/cells12141899

APA Style

Ebert, S., Zang, L., Ismail, N., Otabil, M., Fröhlich, A., Egea, V., Ács, S., Hoeberg, M., Berres, M.-L., Weber, C., Moreira, J. M. A., Ries, C., Bernhagen, J., & El Bounkari, O. (2023). Tissue Inhibitor of Metalloproteinases-1 Interacts with CD74 to Promote AKT Signaling, Monocyte Recruitment Responses, and Vascular Smooth Muscle Cell Proliferation. Cells, 12(14), 1899. https://doi.org/10.3390/cells12141899

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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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