Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140
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ABSTRACT:
PROVIDER: EGAS00001004460 | EGA |
REPOSITORIES: EGA
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Project description:Crohn's disease (CD) is a complex and highly heterogeneous chronic inflammatory disorder, primarily affecting the gastrointestinal tract. Genetic and functional studies have highlighted a key role for innate immunity in its pathogenesis. Profound systemic defects in innate immunity and acute inflammation are understood to result in markedly delayed clearance of bacteria from the tissues, leading to local chronic granulomatous inflammation and compensatory adaptive immunological changes. Macrophages, key orchestrators of acute inflammation, are likely to play an important role in the initial impaired innate immune response. Monocyte-derived macrophages from CD patients stimulated with E. coli were shown to release attenuated levels of TNF and IFNM-NM-3 with normal secretion of IL8, IL10 and IL6. In controls, the secretion of these cytokines was strongly positively correlated, which was not seen with CD macrophages. The transcriptomes of CD and control macrophages were examined in an attempt to understand the molecular basis of this defect. There were no differentially expressed genes identified between the two groups, consistent with genetic heterogeneity; however, a number of molecules were found to be under-expressed in subgroups of CD patients. The most common of these was optineurin (OPTN) which was under-expressed in approximately 10% of the CD patients. Reduced OPTN expression coincided with lower intracellular protein levels and diminished cytokine secretion after bacterial stimulation both in the patients and with siRNA knockdown in THP-1 cells. Identifying and studying subgroups of patients with shared defective gene expression could aid our understanding of the mechanisms underlying highly heterogeneous diseases such as CD. Total RNA obtained from monocyte derived macrophages from Crohn's disease patients (n=58) or healthy volenteers (n=42) were cultured for six days before being stimulated with heat killed E. coli for four hours or left unstimulated.
2014-08-06 | E-GEOD-60083 | biostudies-arrayexpress
Project description:Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol levels. Despite ongoing advances in the prevention and treatment of atherosclerosis 1, cardiovascular disease remains the leading cause of death worldwide 2. Continuous retention of apolipoprotein B-containing lipoproteins in the subendothelial space causes a local overabundance of free cholesterol. Since cholesterol accumulation and deposition of cholesterol crystals (CCs) triggers a complex inflammatory response 3 4, we tested the therapeutic potential of increasing cholesterol solubility in experimental atherogenesis. Here we show that treatment of murine atherosclerosis with the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (CD), a compound that solubilizes lipophilic substances, reduced atherosclerotic plaque size, cholesterol crystal load and promoted plaque regression even under continuing Western diet. CD solubilized CCs and promoted cholesterylester and oxysterol production in macrophages leading to liver X receptor (LXR)-mediated transcriptional reprogramming. CD increased cholesterol efflux from macrophages and substantially augmented reverse cholesterol transport in vivo. Furthermore, CD reduced proinflammatory cytokines in vivo and decreased macrophage responsiveness towards TLR and inflammasome activation. Since CD treatment in humans is safe and CD beneficially affects key pathogenetic factors in atherogenesis it may thus be used clinically to prevent or treat human atherosclerosis .
2016-05-06 | GSE67011 | GEO
Project description:Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol levels. Despite ongoing advances in the prevention and treatment of atherosclerosis 1, cardiovascular disease remains the leading cause of death worldwide 2. Continuous retention of apolipoprotein B-containing lipoproteins in the subendothelial space causes a local overabundance of free cholesterol. Since cholesterol accumulation and deposition of cholesterol crystals (CCs) triggers a complex inflammatory response 3 4, we tested the therapeutic potential of increasing cholesterol solubility in experimental atherogenesis. Here we show that treatment of murine atherosclerosis with the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (CD), a compound that solubilizes lipophilic substances, reduced atherosclerotic plaque size, cholesterol crystal load and promoted plaque regression even under continuing Western diet. CD solubilized CCs and promoted cholesterylester and oxysterol production in macrophages leading to liver X receptor (LXR)-mediated transcriptional reprogramming. CD increased cholesterol efflux from macrophages and substantially augmented reverse cholesterol transport in vivo. Furthermore, CD reduced proinflammatory cytokines in vivo and decreased macrophage responsiveness towards TLR and inflammasome activation. Since CD treatment in humans is safe and CD beneficially affects key pathogenetic factors in atherogenesis it may thus be used clinically to prevent or treat human atherosclerosis .
2016-05-06 | GSE67013 | GEO
Project description:Lipopolysaccharide exposure to macrophages induces an inflammatory response that is heavily regulated at the post-transcriptional level. HuR, ELAVL1, is an RNA binding protein that binds and regulate the maturation and half-life of AU/U rich elements (ARE) containing cytokines and chemokines transcripts, mediating the LPS induced response. Here we investigated to what extent small molecules inhibiting HuR-RNA interaction, called tanshinone mimics, counteract the LPS induced macrophage response. We show that tanshinone mimics are present in solution in a keto-enolic tautomerism and that, by molecular dynamic calculations, the ortho quinone form is the preferred species interacting with HuR and favoring the closure of its conformation to a no-binding mode. The protection of the enolic status with diacetate caused the loss of activity of tanshinone mimics in vitro but active in vivo. Murine macrophages cell line RAW264.7 was treated with LPS and tanshinone mimics and the modulation of the LPS induced response was monitored by RNA and Ribonucleoprotein immunoprecipitation sequencing. Correlation analyses indicated that LPS induced a strong coupling between differentially expressed genes and HuR-bound genes and that tanshinone mimics reduced the interaction. Functional annotation addressed a specific set of genes, as Cxcl10, Il1b, Cd40, Fas, involved in chemotaxis and immune response whose association with HuR decreased and led to a reduction of their protein level and secretion. The same effect was observed in primary murine bone marrow derived macrophages and in vivo in a LPS induced peritonitis model, in which the serum level of Cxcl10 and Il1b was strongly reduced, endowing tanshinone mimics with anti-inflammatory properties in vivo.
2023-03-01 | GSE198605 | GEO
Project description:Crohn's disease (CD) is a complex and highly heterogeneous chronic inflammatory disorder, primarily affecting the gastrointestinal tract. Genetic and functional studies have highlighted a key role for innate immunity in its pathogenesis. Profound systemic defects in innate immunity and acute inflammation are understood to result in markedly delayed clearance of bacteria from the tissues, leading to local chronic granulomatous inflammation and compensatory adaptive immunological changes. Macrophages, key orchestrators of acute inflammation, are likely to play an important role in the initial impaired innate immune response. Monocyte-derived macrophages from CD patients stimulated with E. coli were shown to release attenuated levels of TNF and IFNγ with normal secretion of IL8, IL10 and IL6. In controls, the secretion of these cytokines was strongly positively correlated, which was not seen with CD macrophages. The transcriptomes of CD and control macrophages were examined in an attempt to understand the molecular basis of this defect. There were no differentially expressed genes identified between the two groups, consistent with genetic heterogeneity; however, a number of molecules were found to be under-expressed in subgroups of CD patients. The most common of these was optineurin (OPTN) which was under-expressed in approximately 10% of the CD patients. Reduced OPTN expression coincided with lower intracellular protein levels and diminished cytokine secretion after bacterial stimulation both in the patients and with siRNA knockdown in THP-1 cells. Identifying and studying subgroups of patients with shared defective gene expression could aid our understanding of the mechanisms underlying highly heterogeneous diseases such as CD.
2014-08-06 | GSE60083 | GEO
Project description:We studied macrophage gene expression from mice fed chow diet (C) or 60% high fat diet (HF), that phagocytized C-RBC, HFD-RBC, or no RBC. Macrophages from mice on HF diet were activated toward a pro-inflammatory phenotype. In macrophages isolated from CD mice, RBC phagocytosis yielded a gene expression pattern similar to HF macrophages. Incubation of HF-RBC with macrophages resulted in a significantly more pronounced upregulation of pro-inflammatory chemokines as compared to C-RBC.
2013-08-28 | GSE50240 | GEO
Project description:We studied macrophage gene expression from mice fed chow diet (C) or 60% high fat diet (HF), that phagocytized C-RBC, HFD-RBC, or no RBC. Macrophages from mice on HF diet were activated toward a pro-inflammatory phenotype. In macrophages isolated from CD mice, RBC phagocytosis yielded a gene expression pattern similar to HF macrophages. Incubation of HF-RBC with macrophages resulted in a significantly more pronounced upregulation of pro-inflammatory chemokines as compared to C-RBC. Peritoneal macrophages were obtained from C57BL/6 mice fed either C or HF diet. Phagocytosis was performed in vitro with C-RBC or HF-RBC; macrophages not exposed to RBC served as a control. Affymetrix Mouse Gene 1.0 ST microarray chips were used to assess the gene expression profile.
2013-08-28 | E-GEOD-50240 | biostudies-arrayexpress
Project description:The virulence factor HlyA of Uropathogenic Escherichia coli (UPEC) could modulate host cell metabolism and inhibits NF-κB signaling pathway. However, whether there is a link between these two processes remains elusive. Here, we demonstrated UPEC could suppress metabolic enzyme ATP citrate lyase (ACLY) that resulted into histone deacetylation by decreasing the levels of acetyl-CoA. The level of histone acetylation was rescued supplementation of acetate. Furthermore, using H3 Lysine9 acetylation (H3K9ac) immunoprecipitation coupled next generation sequencing (ChIP-seq), we found that UPEC cause site specific regulation of H3K9ac which correlates with the expression of pro-inflammatory cytokines and chemokines. To be more specific, the expression of pro-inflammatory cytokines and chemokines like IL 8, CXCL2, and IL-1α are suppressed by UPEC mediated decreasing of H3K9ac at TSS-promoter region. Thus, this study established that UPEC manipulate host cell metabolism to impact histone acetylation at specific loci, correlating with cytokines and chemokines expression, as a means to inhibit NF-κB signaling.
2019-05-22 | GSE131560 | GEO
Project description:Diabetic foot ulcers (DFUs) are characterized by a chronic inflammation state which prevents cutaneous wound healing, andDFUs eventually lead to infection and leg amputation. Macrophages located in DFUs are locked in an pro-inflammatory phenotype. In this study, the effect of hyperglycemia and hypoxia on the macrophage phenotype was analyzed. For this purpose, a microarray was performed to study the gene expression profile of macrophages cultivated in a high glucose concentration. Hyperglycemia upregulated the expression of pro-inflammatory cytokines such as TNF-α, IL-1, IL-6, chemokines and downregulatd the expression of two receptors involved in phagocytosis (CD 36 and Class B scavenger type I receptors). In addition, eleven anti-apoptotic factors were upregulated whereas three pro-apoptotic ones were downregulated. Subsequently, the contribution of hypoxia and hyperglycemia to chronic inflammation and their potential synergic effect was evaluated on activated THP-1 derived macrophages. A long term post activation effect (17 hours) was only observed on the upregulation of pro-inflammatory cytokines when hypoxia was combined with a high glucose concentration. In contrast, hyperglycemia and hypoxia did not have any effect on wound healing molecules such as TGF-β1. Taken together, the results show that hyperglycemia acts in synergy with hypoxia to maintain a chronic inflammation state in macrophages.
2019-07-24 | GSE132187 | GEO
Project description:The prohormone convertase 1/3 (PC1/3) is an enzyme playing an important role in the processing of precursor proteins involved in neuroimmune phenotype of neuroendocrine cells. The expression of PC1/3 is not only restricted to neuroendocrine tissues; recent studies reported a role of PC1/3 in Toll-like receptor immune response in macrophages. Here, using lentivirus strategy, we investigated the consequences of PC1/3 down-regulation with the aim of understanding the intracellular impact of such inhibition and its biological application to cancer therapy. Under sterile conditions, we demonstrated that PC1/3 inactivated macrophages express a M1-like phenotype characterized by filopodia extensions, pro-inflammatory chemokines and cytokines secretion (IL6, CXCL10; TNF) and TLR4 Myd88 dependent signaling activation. Under LPS challenge, PC1/3 KO cells secrete through store-operated calcium entry increase, a cocktail of pro-inflammatory factors including alarmins and chemokines conducting to attract naïve T helper lymphocytes (Th0) which favors cytotoxic response. Tests perform with the secreted factors by the challenged PC1/3 KO cells on breast and ovarian cancer cells (SKBR3, SKOV3) establish that the factors secreted are able to inhibit both viability and resistance to chemotherapies. Under inhibitory conditions using IL-10, the PC1/3 KO cells still continue to produce inflammatory cytokines and anti-tumoral factors. Taken together, these data establish that inhibition of PC1/3 can be used as a potential immune therapy for awaking intra-tumoral macrophages.
2015-09-09 | PXD001984 | Pride