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Peripheral immune-derived matrix metalloproteinase promotes stress susceptibility.

ABSTRACT: Psychosocial stress has profound effects on the body, including the peripheral immune system and the brain^1,2. Although a large number of pre-clinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as major depressive disorder (MDD)^3,4,5, the underlying mechanisms are not well understood. Here we show that a peripheral myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is elevated in serum of subjects with MDD as well as in stress-susceptible (SUS) mice following chronic social defeat stress (CSDS). In mice, we show that this increase leads to alterations in extracellular space and neurophysiological changes in the nucleus accumbens (NAc), thereby altering social behaviour. Using a combination of mass cytometry and single-cell RNA-sequencing, we performed high-dimensional phenotyping of immune cells in circulation and brain and demonstrate that peripheral monocytes are strongly affected by stress. Both peripheral and brain-infiltrating monocytes of SUS mice showed increased Mmp8 expression following CSDS. We further demonstrate that peripheral MMP8 directly infiltrates the NAc parenchyma to control the ultrastructure of the extracellular space. Depleting MMP8 prevented stress-induced social avoidance behaviour and alterations in NAc neurophysiology and extracellular space. Collectively, these data establish a novel mechanism by which peripheral immune factors can affect central nervous system function and behaviour in the context of stress. Targeting specific peripheral immune cell-derived matrix metalloproteinases could constitute novel therapeutic targets for stress-related neuropsychiatric disorders.

SUBMITTER: Cathomas F

PROVIDER: S-EPMC9915787 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Peripheral immune-derived matrix metalloproteinase promotes stress susceptibility.

Cathomas Flurin F Lin Hsiao-Yun HY Chan Kenny L KL Li Long L Durand-de Cuttoli Romain R Durand-de Cuttoli Romain R Parise Lyonna F LF Aubry Antonio V AV Muhareb Samer S Desland Fiona F Shimo Yusuke Y Ramakrishnan Aarthi A Estill Molly M Ferrer-Pérez Carmen C Parise Eric M EM Wang Jun J Sowa Allison A Janssen William G WG Costi Sara S Rahman Adeeb A Fernandez Nicolas N Swirski Filip K FK Nestler Eric J EJ Shen Li L Merad Miriam M Murrough James W JW Russo Scott J SJ

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Psychosocial stress has profound effects on the body, including the peripheral immune system and the brain<sup>1,2</sup>. Although a large number of pre-clinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as major depressive disorder (MDD)<sup>3,4,5</sup>, the underlying mechanisms are not well understood. Here we show that a peripheral myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is elevated in serum of subjects ...[more]

PMID: 36778505

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Project description:Background: Tyrosine kinase with immunoglobulin and EGF-like domains 1 (TIE1) is known as an orphan receptor prominently expressed in endothelial cells and participates in angiogenesis by regulating TIE2 activity. Our previous study demonstrated elevated TIE1 expression in cervical cancer cells. However, the role of TIE1 in cervical cancer progression, metastasis and treatment remains elusive. Methods: Immunohistochemistry staining for TIE1 and Basigin was performed in 135 human cervical cancer tissues. Overexpressing vectors and siRNAs were used to manipulate gene expression in tumor cells. Colony formation, wound healing, and transwell assays were used to assess cervical cancer cell proliferation and migration in vitro. Subcutaneous xenograft tumor and lung metastasis mouse models were established to examine tumor growth and metastasis. Co-Immunoprecipitation and Mass Spectrometry were applied to explore the proteins binding to TIE1. Immunoprecipitation and immunofluorescence staining were used to verify the interaction between TIE1 and Basigin. Cycloheximide chase assay and MG132 treatment were conducted to analyze protein stability. Results: High TIE1 expression was associated with poor survival in cervical cancer patients. TIE1 overexpression promoted the proliferation, migration and invasion of cervical cancer cells in vitro, as well as tumor growth and metastasis in vivo. In addition, Basigin, a transmembrane glycoprotein, was identified as a TIE1 binding protein, suggesting a pivotal role in matrix metalloproteinase regulation, angiogenesis, cell adhesion, and immune responses. Knockdown of Basigin or treatment with the Basigin inhibitor AC-73 reversed the tumor-promoting effect of TIE1 in vitro and in vivo. Furthermore, we found that TIE1 was able to interact with and stabilize the Basigin protein and stimulate the Basigin-matrix metalloproteinase axis. Conclusion: TIE1 expression in cervical cells exerts a tumor-promoting effect, which is at least in part dependent on its interaction with Basigin. These findings have revealed a TIE2-independent mechanism of TIE1, which may provide a new biomarker for cervical cancer progression, and a potential therapeutic target for the treatment of cervical cancer patients.

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Peripheral immune-derived matrix metalloproteinase promotes stress susceptibility.

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Peripheral immune-derived matrix metalloproteinase promotes stress susceptibility.

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