Leukotriene B4 receptor 2 governs macrophage migration during tissue inflammation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1014419 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25956200_1.fastq.gz | Fastqsanger.gz | |||
| SRR25956200_2.fastq.gz | Fastqsanger.gz | |||
| SRR25956201_1.fastq.gz | Fastqsanger.gz | |||
| SRR25956201_2.fastq.gz | Fastqsanger.gz | |||
| SRR25956202_1.fastq.gz | Fastqsanger.gz |
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Project description:Chronic inflammation is the underlying cause of many diseases, including type 1 diabetes, obesity, and non-alcoholic fatty liver disease. Macrophages are continuously recruited to tissues during chronic inflammation where they exacerbate or resolve the pro-inflammatory environment. Although leukotriene B4 receptor 2 (BLT2) has been characterized as a low affinity receptor to several key eicosanoids and chemoattractants, its precise roles in the setting of inflammation and macrophage function remain incompletely understood. Here we used zebrafish and mouse models to probe the role of BLT2 in macrophage function during inflammation. We detected BLT2 expression in bone marrow derived and peritoneal macrophages of mouse models. Transcriptomic analysis of Ltb4r2-/- and WT macrophages suggested a role for BLT2 in macrophage migration, and studies in vitro confirmed that whereas BLT2 does not mediate macrophage polarization, it is required for chemotactic function, possibly mediated by downstream genes Ccl5 and Lgals3. Using a zebrafish model of tailfin injury, we demonstrated that antisense morpholino-mediated knockdown of blt2a or chemical inhibition of BLT2 signaling impairs macrophage migration. We further replicated these findings in zebrafish models of islet injury and liver inflammation. Moreover, we established the applicability of our zebrafish findings to mammals by showing that macrophages of Ltb4r2-/- mice have defective migration during lipopolysaccharide stimulation in vivo. Collectively, our results demonstrate that BLT2 mediates macrophage migration during inflammation, which implicates it as a potential therapeutic target for inflammatory pathologies.
2023-12-01 | GSE242723 | GEO
Project description:total RNA from mouse (male c57BL/6) spleen labeled with Cy3 vs total RNA from mouse (male c57BL/6) B cells treated with Leukotriene B4 (LTB4) labeled with Cy5- time course with repeats Keywords: ordered
2003-04-14 | GSE390 | GEO
Project description:Chronic inflammation is the underlying cause of many diseases, including type 1 diabetes, obesity, and non-alcoholic fatty liver disease. Macrophages are continuously recruited to tissues during chronic inflammation where they exacerbate or resolve the pro-inflammatory environment. Although leukotriene B4 receptor 2 (BLT2) has been characterized as a low affinity receptor to several key eicosanoids and chemoattractants, its precise roles in the setting of inflammation and macrophage function remain incompletely understood. Here we used zebrafish and mouse models to probe the role of BLT2 in macrophage function during inflammation. We detected BLT2 expression in bone marrow derived and peritoneal macrophages of mouse models. Transcriptomic analysis of Ltb4r2-/- and WT macrophages suggested a role for BLT2 in macrophage migration, and studies in vitro confirmed that whereas BLT2 does not mediate macrophage polarization, it is required for chemotactic function, possibly mediated by downstream genes Ccl5 and Lgals3. Using a zebrafish model of tailfin injury, we demonstrated that antisense morpholino-mediated knockdown of blt2a or chemical inhibition of BLT2 signaling impairs macrophage migration. We further replicated these findings in zebrafish models of islet injury and liver inflammation. Moreover, we established the applicability of our zebrafish findings to mammals by showing that macrophages of Ltb4r2-/- mice have defective migration during lipopolysaccharide stimulation in vivo. Collectively, our results demonstrate that BLT2 mediates macrophage migration during inflammation, which implicates it as a potential therapeutic target for inflammatory pathologies.
| S-EPMC10790086 | biostudies-literature
Project description:Leukotriene B4 (LTB4) is a potent lipid mediator of inflammation, implicated in numerous diseases including atherosclerosis. We have used primary human monocytes, which express both receptors, to analyze transcriptional responses to LTB4. Comparisons were made between LTB4- and vehicle-treated samples at the same time point. The analysis showed that expression of 72 genes was upregulated at least two-fold at two time points. These genes include multiple chemokines as well as some genes with unknown function. Keywords: time course
2007-10-18 | GSE9332 | GEO
Project description:Human umbilical vein endothelial cells (HUVEC) or the human macrophage cell line, Mono-Mac-6, treated with Leukotriene D4 for 1 hour
2008-06-12 | E-GEOD-1644 | biostudies-arrayexpress
Project description:Human umbilical vein endothelial cells (HUVEC) or the human macrophage cell line, Mono-Mac-6, treated with Leukotriene D4 for 1 hour Keywords = Leukotriene-Transcriptome Keywords = Mono-Mac-6 Keywords = HUVEC Keywords: other
2004-08-20 | GSE1644 | GEO
Project description:Timely inhibition of inflammation and initiation of resolution are important for the repair of injured tissues. Pharmacological inhibition of mammalian STE20-like protein kinase 1/2 (MST1/2) with XMU-MP-1 might augment tissue regeneration and repair by suppressing apoptosis and increasing cell proliferation. However, MST1 has anti-inflammatory activity, inhibition of which may result in therapy failure. Here, we identified an approach with the potential to overcome this limitation by protecting against cardiac inflammation resulting from inhibition of MST1 in macrophages. We found exacerbation of cardiac dysfunction in LysMCre-mediated Mst1/2-deficient mice after myocardial infarction (MI). This effect was attributed to a shift of macrophage subtypes from those expressing Cxcl2 and Cd163 toward those with Ccl2 and Ccl4 expression. Mass spectrometry identified leukotriene B4 (LTB4) as the lipid mediator that was upregulated in the absence of MST1. We found that MST1 phosphorylated 5-lipoxygenase (5-LOX) at its T218 residue, disrupting the interaction between 5-LOX and 5-LOX-activating protein, and resulting in reduction of LTB4 production. By contrast, a 5-LOXT218A variant showed no response to MST1. Moreover, treatment of peritoneal macrophages with LTB4 or with medium conditioned by Mst1-deficient macrophages resulted in high Ccl2 and Ccl4 expression and low Cxcl2 and Cd163 expression, except when the cells were co-treated with the LTB4 receptor 1 (BLT1) antagonist CP105696. Furthermore, CP105696 ameliorated cardiac dysfunction in LysMCre-mediated Mst1/2-deficient mice and enhanced cardiac repair in wild-type mice treated with XMU-MP-1 after MI. The combination of an MST1/2 inhibitor and a BLT1 antagonist represents a promising strategy for combatting the effects of MI.
2021-12-13 | GSE181935 | GEO
Project description:Pulmonary hypertension (PH) is a serious condition that affects mainly young and middle-aged women, and its etiology is poorly understood. A prominent pathological feature of PH is accumulation of macrophages near the arterioles of the lung. In both clinical tissue and the SU5416 (SU)/athymic rat model of severe PH, we found that the accumulated macrophages expressed high levels of leukotriene A4 hydrolase (LTA4H), the biosynthetic enzyme for leukotriene B4 (LTB4). Moreover, macrophage-derived LTB4 directly induced apoptosis in pulmonary artery endothelial cells (PAECs). Further, LTB4 induced proliferation and hypertrophy of human pulmonary artery smooth muscle cells. We found that LTB4 acted through its receptor, BLT1, to induce PAEC apoptosis by inhibiting the protective endothelial sphingosine kinase 1 (Sphk1)-endothelial nitric oxide synthase (eNOS) pathway. Blocking LTA4H decreased in vivo LTB4 levels, prevented PAEC apoptosis, restored Sphk1-eNOS signaling, and reversed fulminant PH in the SU/athymic rat model of PH. Antagonizing BLT1 similarly reversed established PH. Inhibition of LTB4 biosynthesis or signal transduction in SU-treated athymic rats with established disease also improved cardiac function and reopened obstructed arterioles; this approach was also effective in the monocrotaline model of severe PH. Human plexiform lesions, one hallmark of PH, showed increased numbers of macrophages, which expressed LTA4H, and patients with connective tissue disease-associated pulmonary arterial hypertension exhibited significantly higher LTB4 concentrations in the systemic circulation than did healthy subjects. These results uncover a possible role for macrophage-derived LTB4 in PH pathogenesis and identify a pathway that may be amenable to therapeutic targeting.
| S-EPMC4016764 | biostudies-literature
Project description:The capacity of dendritic cells (DC) to migrate from peripheral organs to lymph nodes (LN) is an important event in the initiation of a T cell-mediated immune response. Previously it was shown that the ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp; ABCB1) and the 2 multidrug resistance protein 1 (MRP1; ABCC1) play a role in both human and murine DC migration. Here we show that a more recently discovered family-member, MRP4 (ABCC4) is expressed on both epidermal and dermal human skin DC and contributes to the migratory capacity of DC. Pharmacological inhibition of MRP4 activity or down-regulation through RNAi in DC resulted in reduced migration of DC from human skin explants and of in vitro generated Langerhans cells. The responsible MRP4 substrate remains to be identified as exogenous addition of MRP4’s known substrates PGE2, leukotriene B4 and D4 or cyclic nucleotides (all previously implicated in DC migration) could not restore migration. This notwithstanding, our data show that MRP4 is an important molecule, significantly contributing to human DC migration towards the draining lymph nodes, and thereby relevant for the initiation of an immune response and a possible target for immunotherapy. Keywords: cell type comparison, RNAi knockdown for MRP4 2 samples were analyzed to compare. Immature DC cultured from MUTZ3 (reference control) or from MUTZ3-shMRP4 cells
2008-07-12 | E-GEOD-12089 | biostudies-arrayexpress
Project description:Background: Cysteinyl leukotrienes (cysLTs) are important mediators of innate immune responsiveness and chronic inflammatory diseases. CysLTs acting through cysteinyl leukotriene receptors may influence the migration and activity of cells such as eosinophils, monocytes and dendritic cells. Objective: To determine the gene expression signature of human monocytes in response to cysLTs and to elucidate the signaling pathways involved in monocyte activation. Methods: Gene expression was analyzed using oligonucleotide microarrays. Responsiveness to cysLTs was assessed by real-time PCR, calcium flux, kinase activation and chemotaxis assays. Results: Cysteinyl leukotriene type I receptor (CysLTR1) transcript 1 is predominantly expressed in human monocytes and cysLTs signal through CysLTR1 in these cells. Several immediate-early genes, including early growth response (Egr) -2, 3, FosB, activating transcription factor 3 and nuclear receptor subfamily 4 were significantly induced by LTD4. This effect was mediated by CysLTR1 coupled to Gαi/o, activation of phospholipase C, and inositol-1,4,5-triphosphate (IP3) and store operated calcium channels. LTD4 induced p38 MAP kinase phosphorylation, a pathway also involved in the regulation of immediate-early genes expression in monocytes. LTD4 stimulated monocyte chemotactic activity that was fully blocked by a selective CysLTR1 inhibitor MK571 and pertussis toxin, suggesting that CysLTR1 coupled to Gαi/o is a dominant functional pathway in human monocytes. Conclusion: Our data show that cysLTs acting through CysLTR1 can significantly influence the activation and migration of human monocytes and that these effects can be fully inhibited by CysLTR1 antagonists. Clinical implications: Antileukotriene therapies are likely to significantly block the proinflammatory functions of human monocytes. Experiment Overall Design: 4 control sample, 4 LTD4 stimulated samples
2008-06-15 | E-GEOD-7807 | biostudies-arrayexpress