The matricellular protein SPARC induces inflammatory interferon-response in macrophages during aging
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE167950 | GEO | 2022/08/12
REPOSITORIES: GEO
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Project description:Effects of the matricellular protein CCN1 on macrophage inflammatory gene expression was tested in a macrophage cell line I-13.35. CCN1 (CYR61) is a matricellular protein that is highly expressed at sites of inflammation and wound repair. In these contexts, CCN1 can modify the activities of specific cytokines, enabling TNF-alpha to be cytotoxic without blocking NFkB activity and enhancing the apoptotic activity of FasL and TRAIL. Here we show that CCN1 supports the adhesion of macrophages through integrin alphaMbeta2 and syndecan-4, activates NFkB-mediated transcription, and induces a pro-inflammatory genetic program characteristic of classically activated M1 macrophages that participates in Th1 responses. The effects of CCN1 include upregulation of cytokines (TNFa, IL-1a, IL-1b, IL-6, IL-12b), chemokines (MIP-1a, MCP-3, Gro1, Gro2, IP-10), regulators of oxidative stress and complement (iNOS, C3), and downregulation of specific receptors (TLR4, IL-10rb) and anti-inflammatory factors (TGF-b1). CCN1 regulates this genetic program through at least two distinct mechanisms: an immediate-early response resulting from direct activation of NFkB by CCN1, leading to the synthesis of cytokines including TNFa and IP-10; and a delayed response resulting from CCN1-induced TNFa, which acts as an autocrine/paracrine mediator to activate the expression of other cytokines including IL-1b and IL-6. These results identify CCN1 as a novel component of the extracellular matrix that activates pro-inflammatory genes in macrophages, implicating its role in regulating macrophage function during inflammation. Macrophage cell line I-13.35 (from Tlr4-defective C3H/HeJ) was treated with purified recombinant CCN1 protein for 6 hr. Total RNA was isolated, converted to cRNA probes, and hybridized to a oligonucleotide array representing 113 murine inflammation-related genes (from SA Biosciences at www.sabiosciences.com, Cat. Number OMM-011.) The array is a nylon membrane based DNA microarray on which 60-mer oligonucleotides probes were printed. Gene expression profile of resting cells incubated in serum-free medium (containing albumin, BSA) was used as a control for basal levels of gene expression.
2010-05-14 | E-GEOD-19731 | biostudies-arrayexpress
Project description:The matricellular protein SPARC induces inflammatory interferon-response in macrophages during aging
| PRJNA705658 | ENA
Project description:The remodeling of the extracellular matrix (ECM) by proteases releases fragments that promote tumor progression and metastasis. The protease cathepsin D (cath-D), a marker of poor prognosis in triple-negative breast cancer (TNBC), is aberrantly secreted in the ECM. Using degradomics, we discovered that the matricellular protein SPARC is a substrate of extracellular cath-D. In vitro, cath-D induced limited proteolysis of SPARC C-terminal extracellular Ca2+ binding domain at acidic pH, leading to the production of SPARC fragments (34-, 27-, 16-, 9-, and 6-kDa). Cath-D secreted by TNBC cells cleaved fibroblast- and cancer cell-derived SPARC at the tumor pericellular pH. SPARC cleavage also occurred in TNBC tumors. Among these fragments, the 9-kDa SPARC fragment inhibited TNBC cell adhesion and spreading, and stimulated their migration, endothelial transmigration and invasion more potently than full-length SPARC. Our study establishes a novel crosstalk between proteases and matricellular proteins in the ECM through limited proteolysis of SPARC, revealing a novel targetable 9-kDa bioactive SPARC fragment for TNBC.
2021-09-09 | PXD022826 | Pride
Project description:Effects of the matricellular protein CCN1 on macrophage inflammatory gene expression was tested in a macrophage cell line I-13.35. CCN1 (CYR61) is a matricellular protein that is highly expressed at sites of inflammation and wound repair. In these contexts, CCN1 can modify the activities of specific cytokines, enabling TNF-alpha to be cytotoxic without blocking NFkB activity and enhancing the apoptotic activity of FasL and TRAIL. Here we show that CCN1 supports the adhesion of macrophages through integrin alphaMbeta2 and syndecan-4, activates NFkB-mediated transcription, and induces a pro-inflammatory genetic program characteristic of classically activated M1 macrophages that participates in Th1 responses. The effects of CCN1 include upregulation of cytokines (TNFa, IL-1a, IL-1b, IL-6, IL-12b), chemokines (MIP-1a, MCP-3, Gro1, Gro2, IP-10), regulators of oxidative stress and complement (iNOS, C3), and downregulation of specific receptors (TLR4, IL-10rb) and anti-inflammatory factors (TGF-b1). CCN1 regulates this genetic program through at least two distinct mechanisms: an immediate-early response resulting from direct activation of NFkB by CCN1, leading to the synthesis of cytokines including TNFa and IP-10; and a delayed response resulting from CCN1-induced TNFa, which acts as an autocrine/paracrine mediator to activate the expression of other cytokines including IL-1b and IL-6. These results identify CCN1 as a novel component of the extracellular matrix that activates pro-inflammatory genes in macrophages, implicating its role in regulating macrophage function during inflammation.
2010-02-18 | GSE19731 | GEO
Project description:The cells and mechanisms involved in blood clot resorption are only partially known. Regulatory T cells (Treg) accumulate in venous blood clots and regulate thrombolysis by controlling the recruitment, differentiation and matrix metalloproteinase (MMP) activity of monocytes. The clot Treg population is heterogeneous and contains a population of Treg that forms the matricellular acid- and cysteine-rich protein (SPARC). SPARC induces MMP activity in monocytes and SPARC+ Treg are required for clot resorption.
2023-06-01 | GSE155444 | GEO
Project description:SPARC is a matricellular glycoprotein involved in regulation of the extracellular matrix, growth factors, adhesion, and migration. SPARC-null mice have altered basement membranes and develop posterior sub-capsular cataracts with cell swelling and equatorial vacuoles. Exchange of fluid, nutrients, and waste products in the avascular lens is driven by a unique circulating ion current. Here we demonstrate that SPARC-null mouse lenses exhibit abnormal circulation of fluid, ion, and small molecules which leads to altered fluorescein distribution in vivo, loss of resting membrane polarization, and altered distribution of small molecules. Microarray analysis of SPARC-null lenses showed changes in gene expression of ion channels and receptors, matrix and adhesion genes, cytoskeleton, immune response genes, and cell signaling molecules. Our results demonstrate that the regulation of SPARC on cell-capsular matrix interactions can influence the circulation of fluid and ions in the lens, and the phenotype in the SPARC-null mouse lens is the result of multiple intersecting pathways. Experiment Overall Design: Lens epithelial cells from 7 lenses of littermate mice were isolated by laser capture microdissection. 3 wild-type lenses from 3 different mice and 4 knock-out lenses from 3 different mice were used as biological replicates.
2009-05-11 | E-GEOD-13402 | biostudies-arrayexpress
Project description:SPARC is a matricellular glycoprotein that plays critical roles in the pathologies associated with obesity and diabetes, as well as tumorigenesis. The objective of this study was to investigate the role of SPARC in the process of trophoblast invasion which shares many similarities with tumor cells invasion. Our results reveals that hormones, cell adhesion molecules, ECM molecules, growth factors and cytokines all are mediated by SPARC in EVT invasion. HTR-8/SVneo cells were transfected with SPARC siRNA or a 25-nucleotide universal negative control siRNA using Lipofectamine 2000 according to the manufacturer’s protocol. Seventy-two hours after transfection, cells were harvested and RNA was isolated using standard procedures.
2012-04-27 | E-GEOD-37639 | biostudies-arrayexpress
Project description:SPARC is a matricellular glycoprotein involved in regulation of the extracellular matrix, growth factors, adhesion, and migration. SPARC-null mice have altered basement membranes and develop posterior sub-capsular cataracts with cell swelling and equatorial vacuoles. Exchange of fluid, nutrients, and waste products in the avascular lens is driven by a unique circulating ion current. Here we demonstrate that SPARC-null mouse lenses exhibit abnormal circulation of fluid, ion, and small molecules which leads to altered fluorescein distribution in vivo, loss of resting membrane polarization, and altered distribution of small molecules. Microarray analysis of SPARC-null lenses showed changes in gene expression of ion channels and receptors, matrix and adhesion genes, cytoskeleton, immune response genes, and cell signaling molecules. Our results demonstrate that the regulation of SPARC on cell-capsular matrix interactions can influence the circulation of fluid and ions in the lens, and the phenotype in the SPARC-null mouse lens is the result of multiple intersecting pathways.
2009-05-01 | GSE13402 | GEO
Project description:Fatal neuroendocrine (NE) prostate cancer evolves from castration-resistant adenocarcinoma as a mechanism of resistance to androgen deprivation/anti androgen receptor therapies. Evidence suggests the microenvironment as a possible source of soluble factors mediating neuroendocrine differentiation (NED), but molecular mechanisms are unknown. Using a transgenic mouse model we show that upon castration tumor cells up-regulate GRP78, which triggers a cascade leading to down-regulation of the matricellular protein SPARC in the nearby stroma. SPARC loss allows stroma cells to release IL-6, a known inducer of NED. A drug targeting GRP78 blocks NED in castrated mice. These events find correlation in prostate cancer patients developing focal NED after androgen deprivation therapies. Our results candidate SPARC and GRP78 for diagnostic and therapeutic purpose, respectively.
2021-07-30 | GSE156033 | GEO
Project description:Dunster2014 - WBC Interactions (Model1)
This is a sub-model of a three-step
inflammatory response modelling study. The model includes distinct
populations of white blood cells namely, macrophages and active and
apoptotic neutrophil populations. Neutrophil apoptosis rate is
predicted to be crucial for the qualitative nature of the
system.
This model is described in the article:
The resolution of
inflammation: a mathematical model of neutrophil and macrophage
interactions.
Dunster JL, Byrne HM, King JR.
Bull. Math. Biol. 2014 Aug; 76(8):
1953-1980
Abstract:
There is growing interest in inflammation due to its
involvement in many diverse medical conditions, including
Alzheimer's disease, cancer, arthritis and asthma. The
traditional view that resolution of inflammation is a passive
process is now being superceded by an alternative hypothesis
whereby its resolution is an active, anti-inflammatory process
that can be manipulated therapeutically. This shift in mindset
has stimulated a resurgence of interest in the biological
mechanisms by which inflammation resolves. The
anti-inflammatory processes central to the resolution of
inflammation revolve around macrophages and are closely related
to pro-inflammatory processes mediated by neutrophils and their
ability to damage healthy tissue. We develop a spatially
averaged model of inflammation centring on its resolution,
accounting for populations of neutrophils and macrophages and
incorporating both pro- and anti-inflammatory processes. Our
ordinary differential equation model exhibits two outcomes that
we relate to healthy and unhealthy states. We use bifurcation
analysis to investigate how variation in the system parameters
affects its outcome. We find that therapeutic manipulation of
the rate of macrophage phagocytosis can aid in resolving
inflammation but success is critically dependent on the rate of
neutrophil apoptosis. Indeed our model predicts that an
effective treatment protocol would take a dual approach,
targeting macrophage phagocytosis alongside neutrophil
apoptosis.
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2024-09-02 | BIOMD0000000616 | BioModels