Peripheral immune-derived matrix metalloproteinase promotes stress susceptibility
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA836902 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Psychosocial stress has profound effects on the body, including the peripheral immune system and the brain1,2. 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 myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is elevated in serum from MDD subjects 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 behavior. 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 show increased expression of Mmp8 following CSDS. We further show that peripheral MMP8 directly infiltrates the NAc parenchyma to control ultrastructure of the extracellular space. Depleting MMP8 prevented stress-induced social avoidance behavior 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 behavior in the context of stress. Targeting specific peripheral immune cell-derived proteins, such as matrix metalloproteinases, could constitute novel therapeutic targets for stress-related neuropsychiatric disorders.
2023-02-24 | GSE202662 | GEO
Project description:Psychosocial stress has profound effects on the body, including the peripheral immune system and the brain1,2. 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.
| S-EPMC9915787 | biostudies-literature
Project description:Recently, it was shown that the Bmp antagonist Noggin could strongly induce cardiomyocyte differentiation by transient treatment of undifferentiated ES cells. In order to determine how Noggin may induce cardiac differentiation, we compared differentially expressed genes during Noggin treatment of ES cells using microarray analysis and found that matrix metalloproteinase (Mmp)-3 is the only gene whose expression is increased by Noggin treatment. Keywords: embryonic stem cells, cardiac differentiation, matrix metalloproteinase-3, Noggin
2007-12-18 | GSE8328 | GEO
Project description:Remyelination is a key step in functional nerve regeneration performed by Schwann cells (SC). We have demonstrated that matrix metalloproteinase (MMP)-9 is a major regulator of signal transduction and phenotypic switching in SCs. Herein, genome-wide transcriptional profiling, followed by Ingenuity Pathway Analysis revealed the MMP-9 signaling network and its endogenous inhibitor, TIMP-1, among the top induced genes of the injured sciatic nerve, that co-distributed with MMP-9 in myelinating SCs and the paranodal/nodal areas of myelinated fibers. Homo- and heterodimers of the active and proMMP-9 were purified from injured nerves using gelatin-sepharose. MMP-9 gene deletion increased the number of immature, GFAP+ mSC and post-mitotic cell counts that correlate with shorter myelin internodes in remyelinated fibers lacking MMP-9. MMP-9 is essential to nodal clustering of voltage-gated Na+ (Nav) channels. MMP inhibitor therapy diminished the expression of Nav 1.7 and 1.8. These data established the essential role of MMP-9 in guiding SC differentiation toward myelin production and in molecular assembly of the myelin domains. Modification of Nav channels in myelinated fibers may thus provide an important therapeutic approach for a number of facilitates regeneration and attenuated neuropathic pain. Gene expression profiling of total RNAs extracted from murine sciatic nerves, dorsal root ganglion and spinal cords at day 1 and day 5 post injury.
2012-02-28 | E-GEOD-33454 | biostudies-arrayexpress
Project description:Remyelination is a key step in functional nerve regeneration performed by Schwann cells (SC). We have demonstrated that matrix metalloproteinase (MMP)-9 is a major regulator of signal transduction and phenotypic switching in SCs. Herein, genome-wide transcriptional profiling, followed by Ingenuity Pathway Analysis revealed the MMP-9 signaling network and its endogenous inhibitor, TIMP-1, among the top induced genes of the injured sciatic nerve, that co-distributed with MMP-9 in myelinating SCs and the paranodal/nodal areas of myelinated fibers. Homo- and heterodimers of the active and proMMP-9 were purified from injured nerves using gelatin-sepharose. MMP-9 gene deletion increased the number of immature, GFAP+ mSC and post-mitotic cell counts that correlate with shorter myelin internodes in remyelinated fibers lacking MMP-9. MMP-9 is essential to nodal clustering of voltage-gated Na+ (Nav) channels. MMP inhibitor therapy diminished the expression of Nav 1.7 and 1.8. These data established the essential role of MMP-9 in guiding SC differentiation toward myelin production and in molecular assembly of the myelin domains. Modification of Nav channels in myelinated fibers may thus provide an important therapeutic approach for a number of facilitates regeneration and attenuated neuropathic pain.
2012-02-28 | GSE33454 | GEO
Project description:Esophageal squamous cell carcinoma (ESCC) patients are usually diagnosed at late stages, prohibiting the chance of surgical cure. The obstacle partly comes from the lack of molecular markers for early detection. Moreover, there is no consensus about endoscopic surveillance for ESCC. This study aimed to identify noninvasive markers for ESCC detection. By microarray-based screening of 17 pairs of human ESCC specimens, we identified that secreted protein matrix metalloproteinase-1 (MMP1) may be associated with the presence of ESCC. The tumor and adjacent normal tissues were obtained from 17 male ESCC patients who underwent total esophagectomy without previous cancer treatment at Kaohsiung Medical University Hospital (KMUH)
2015-07-01 | E-GEOD-70409 | biostudies-arrayexpress
Project description:Esophageal squamous cell carcinoma (ESCC) patients are usually diagnosed at late stages, prohibiting the chance of surgical cure. The obstacle partly comes from the lack of molecular markers for early detection. Moreover, there is no consensus about endoscopic surveillance for ESCC. This study aimed to identify noninvasive markers for ESCC detection. By microarray-based screening of 17 pairs of human ESCC specimens, we identified that secreted protein matrix metalloproteinase-1 (MMP1) may be associated with the presence of ESCC.
2015-07-01 | GSE70409 | GEO
Project description:Alcaligenes faecalis corrects aberrant matrix metalloproteinase expression to promote re-epithelialization of diabetic wounds
| PRJNA1086913 | ENA
Project description:CDK8 Mediator kinase is amplified and overexpressed in colon cancers; elevated CDK8 expression is associated with shorter patient survival. Nevertheless, CDK8 kinase inhibitors do not generally suppress colon cancer growth. We addressed this paradox by investigating the effects of CDK8 knockdown or a CDK8 kinase inhibitor on tumor growth at primary and metastatic sites. CDK8 knockdown or inhibition had no significant effect on primary tumors but suppressed the growth of hepatic metastases in murine and human colon cancer models. The effect of CDK8 inhibition on liver metastasis is mediated by upregulation of matrix metalloproteinase (MMP) inhibitor TIMP3 and downregulation of several MMPs.
2017-10-16 | GSE104963 | GEO
Project description:CDK8 Mediator kinase is amplified and overexpressed in colon cancers; elevated CDK8 expression is associated with shorter patient survival. Nevertheless, CDK8 kinase inhibitors do not generally suppress colon cancer growth. We addressed this paradox by investigating the effects of CDK8 knockdown or a CDK8 kinase inhibitor on tumor growth at primary and metastatic sites. CDK8 knockdown or inhibition had no significant effect on primary tumors but suppressed the growth of hepatic metastases in murine and human colon cancer models. The effect of CDK8 inhibition on liver metastasis is mediated by upregulation of matrix metalloproteinase (MMP) inhibitor TIMP3 and downregulation of several MMPs.
2017-09-01 | GSE103346 | GEO