Next Generation Sequencing Facilitates Quantitative Analysis of the implication of LAIR-1 in sorted lung macrophage Transcriptomes
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE216259 | GEO | 2023/09/01
REPOSITORIES: GEO
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Project description:Type-2 innate lymphoid cells (ILC2s) are central players in type-2 asthma. They initiate eosinophil infiltration and airway hyperreactivity (AHR) through cytokine secretion. Leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) is an inhibitory receptor considered as immune checkpoint in different inflammatory diseases. Here we assessed the role of LAIR-1 in murine ILC2s. WT and LAIR-1 KO mice were intranasally challenged with IL-33 and pulmonary ILC2s were sorted to perform RNA sequencing. Our results unravel a novel regulatory axis in ILC2s with the capacity to reduce their activation.
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Project description:Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common life-threatening critical syndrome with no effective pharmacotherapy. Extracellular vesicles (EVs) are considered as a new way of long-distance communication between cells. Our previous research using an ex vivo perfused human ALI model suggested that endothelial cell-derived EVs (EC-EVs) mediate the development of ALI/ARDS. However, how EC-EVs aggravate lung injury remains largely unknown. Here we demonstrated that EC-EVs released under inflammatory stimulation are preferentially taken up by monocytes and reprogram the differentiation of monocytes towards M1 type macrophage. These findings demonstrate a previously unidentified mechanism by which distant infections could lead to ALI/ARDS, providing novel targets and strategies for the prevention and treatment of sepsis-related ALI/ARDS.
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Project description:Background: Acute Respiratory Distress Syndrome (ARDS) or its earlier stage Acute lung injury (ALI), is a worldwide health concern that jeopardizes human well-being. Currently, the treatment strategies to mitigate the incidence and mortality of ARDS are severely restricted. This limitation can be attributed, at least in part, to the substantial variations in immunity observed in individuals with this syndrome. Methods: Bulk and single cell RNA sequencing from ALI mice and single cell RNA sequencing from ARDS patients were analyzed. We utilized the Seurat program package in R and cellmarker 2.0 to cluster and annotate the data. The differential, enrichment, protein interaction, and cell-cell communication analysis were conducted. Results: The mice with ALI caused by pulmonary and extrapulmonary factors demonstrated differential expression including Clec4e, Retnlg, S100a9, Coro1a, and Lars2. We have determined that inflammatory factors have a greater significance in extrapulmonary ALI, while multiple pathways collaborate in the development of pulmonary ALI. Clustering analysis revealed significant heterogeneity in the relative abundance of immune cells in different ALI models. The autocrine action of neutrophils plays a crucial role in pulmonary ALI. Additionally, there was a significant increase in signaling intensity between B cells and M1 macrophages, NKT cells and M1 macrophages in extrapulmonary ALI. The CXCL, CSF3 and MIF, TGFβ signaling pathways play a vital role in pulmonary and extrapulmonary ALI, respectively. Moreover, the analysis of human single-cell revealed DCs signaling to monocytes and neutrophils in COVID-19-related ARDS is stronger compared to sepsis-associated ARDS. In sepsis-associated ARDS, CD8+ T and Th cells exhibit more prominent signaling to B-cell nucleated DCs. Meanwhile, both MIF and CXCL signaling pathways are specific to sepsis-associated ARDS. Conclusions: This study has identified specific gene signatures and signaling pathways in animal models and human samples that facilitate the interaction between immune cells, which could be targeted therapeutically in ARDS patients of various etiologies.
2024-04-24 | GSE264032 | GEO
Project description:Background: Acute Respiratory Distress Syndrome (ARDS) or its earlier stage Acute lung injury (ALI), is a worldwide health concern that jeopardizes human well-being. Currently, the treatment strategies to mitigate the incidence and mortality of ARDS are severely restricted. This limitation can be attributed, at least in part, to the substantial variations in immunity observed in individuals with this syndrome. Methods: Bulk and single cell RNA sequencing from ALI mice and single cell RNA sequencing from ARDS patients were analyzed. We utilized the Seurat program package in R and cellmarker 2.0 to cluster and annotate the data. The differential, enrichment, protein interaction, and cell-cell communication analysis were conducted. Results: The mice with ALI caused by pulmonary and extrapulmonary factors demonstrated differential expression including Clec4e, Retnlg, S100a9, Coro1a, and Lars2. We have determined that inflammatory factors have a greater significance in extrapulmonary ALI, while multiple pathways collaborate in the development of pulmonary ALI. Clustering analysis revealed significant heterogeneity in the relative abundance of immune cells in different ALI models. The autocrine action of neutrophils plays a crucial role in pulmonary ALI. Additionally, there was a significant increase in signaling intensity between B cells and M1 macrophages, NKT cells and M1 macrophages in extrapulmonary ALI. The CXCL, CSF3 and MIF, TGFb signaling pathways play a vital role in pulmonary and extrapulmonary ALI, respectively. Moreover, the analysis of human single-cell revealed DCs signaling to monocytes and neutrophils in COVID-19-associated ARDS is stronger compared to sepsis-related ARDS. In sepsis-related ARDS, CD8+ T and Th cells exhibit more prominent signaling to B cell nucleated DCs. Meanwhile, both MIF and CXCL signaling pathways are specific to sepsis-related ARDS. Conclusion: This study has identified specific gene signatures and signaling pathways in animal models and human samples that facilitate the interaction between immune cells, which could be targeted therapeutically in ARDS patients of various etiologies.
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Project description:Acute Lung Injury (ALI) can cause Acute Respiratory Distress Syndrome (ARDS), a lethal condition with limited treatment options and currently a common global cause of death due to COVID-19-induced ALI. ARDS secondary to Transfusion-Related Acute Lung Injury (TRALI) has been recapitulated pre-clinically by anti-MHC-I antibody administration to LPS-primed mice. In this model, we demonstrated that inhibitors of PTP1B, a protein tyrosine phosphatase that regulates signaling pathways of fundamental importance to homeostasis and inflammation, prevented lung injury and increased survival. Treatment with PTP1B inhibitors attenuated the aberrant neutrophil function that drives ALI, and was associated with release of myeloperoxidase, suppression of Neutrophil Extracellular Trap (NET) formation, and inhibition of neutrophil migration. Mechanistically, reduced signaling through the CXCR4 chemokine receptor, particularly to the activation of mTOR, was essential for these effects, linking PTP1B in hibition to promoting an aged neutrophil phenotype. Considering dysregulated activation of neutrophils is implicated in sepsis and can cause collateral tissue damage, we demonstrated also that PTP1B inhibitors improved survival and ameliorated lung injury in the LPS-induced sepsis model. Our data highlight PTP1B inhibition for prevention of TRALI and ARDS from multiple etiologies.
2021-09-18 | GSE184197 | GEO
Project description:With advances in supportive therapy in the last two decades, mortality rates from ALI/ARDS have improved somewhat, but remain around 30 to 40% with significant morbidity in survivors. Several promising treatments are in various stages of evaluation, but many have failed to prove beneficial in large randomized clinical trials (RCT). The first definitive step forward in ALI therapeutics occurred recently as a result of a large RCT demonstrating a mortality decrease from 40 to 31% with the use of low-volume ventilation strategies. From this, it is clear that the opportunity for successful intervention in ALI exists. However, therapeutic advances remain frustrated by the lack of complete understanding of ALI pathophysiology. This stresses the importance of integrating basic and clinical research of the molecular pathogenesis of this disease. The conclusions of a recent National Heart, Lung, and Blood Institute (NHLBI) Working Group on ALI support this type of research as a priority for future investigations of ALI. One of the areas of research given priority by this ALI Working Group is the issue of ALI severity progression and the role of cells of innate immunity in this process. Currently, the processes that determine which ALI patients progress to ARDS and which do not are unclear. As with many phenotype differences, there is most likely a genetic component involved. The basis for this has been demonstrated. For example, a surfactant protein B (SP-B) polymorphism appears to increase a patientâ??s risk of developing ALI from pneumonia. Additionally, a polymorphism in the promoter region of the gene for interleukin-6 (IL-6) has been associated with a poor prognosis in patients with ARDS. Understanding the intracellular processes of these genes and the cells expressing them in ALI progression could lead to the identification of molecular markers of ALI severity and eventually to the development of targeted therapies. An examination of genetically uniform animals will provide a clearer insight into the interaction between immune cells in ALI progression as well as guide future human experiments. Experiment Overall Design: Specific Aim 1. We will prospectively collect and bank RNA from peripheral blood CD4+ T lymphocytes (Th1 and Th2 subsets) and platelets from cecal ligation and puncture-treated BALB/c mice using a negative selection technique. Specific Aim 2. Four mice will undergo whole blood sampling at each of 3 time points (t = 0, 24, and 48 hours). Time 0 represents the point of CLP. Specific Aim 3. The temporal series of 3 cell types pooled within each time point will be expression profiled (3 time points x 3 cell types x MOE430A array = 9 profiles) in order to generate a map of potential cell-cell interactions and a prioritization model for examining these further.
2008-06-11 | E-GEOD-10343 | biostudies-arrayexpress
Project description:<p>Acute Respiratory Distress Syndrome (ARDS)/ Acute Lung Injury (ALI) is a syndrome defined by the presence of acute hypoxemic respiratory failure, bilateral pulmonary infiltrates on chest radiograph, a known clinical risk factor (e.g. sepsis, pneumonia, trauma, gastric fluid aspiration, pancreatitis, massive transfusion), and the absence of physiologic or clinical evidence of congestive heart failure.</p> <p>The Identification of SNPs Predisposing to Altered ALI Risk (iSPAAR) study is a multi-institutional cooperative study, funded through the NHLBI Recovery Act, that assembled samples and phenotype information from existing cohorts.</p> <p>The consortium included samples from patients with ARDS from the NIH NHLBI ARDS Clinical Trials Network (ARDSNet). Samples were obtained from 3 interventional treatment trials in patients with ARDS, including the Fluid and Catheter Treatment Trial (FACTT), the Albuterol to Treat Acute Lung Injury (ALTA) trial, and the Omega-3 Fatty Acid/Antioxidant Supplementation for ALI trial (Omega).</p> <p>In addition to ARDSnet samples, samples from the other cohorts included cases of established ARDS but also controls: critically ill patients who were at-risk for ARDS but who did not develop ARDS during their hospital course. These cohorts included the Molecular Epidemiology of Acute Respiratory Distress (MEA) Study enrolled at the Harvard University/Massachusetts General Hospital, the Systemic Inflammatory Immune Response Syndrome (SIRS) Patient Database and ICU Traumatic Injury cohorts from Harborview Medical Center, and cohorts collected from the ALI research programs at the University of Pennsylvania and the University of California, San Francisco.</p> <p><b>The Cohort is utilized in the following dbGaP sub-studies.</b> To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" box located on the right hand side of this top-level study page <a href="study.cgi?study_id=phs000631">phs000631</a> ARDSnet iSPAAR Consortium. <ul> <li><a href="study.cgi?study_id=phs000334">phs000334</a> ESP_LungGO_ALI </li> <li><a href="study.cgi?study_id=phs000686">phs000686</a> ALI_GeneticRisk </li> </ul> </p>
| phs000631 | dbGaP
Project description:Acute lung injury (ALI), ARDS and COVID-19 usually involve a “cytokine storm”. IGF1R (Insulin-like growth factor receptor 1) maintains lung homeostasis and is implicated in these pulmonary inflammatory diseases. In mice, widespread IGF1R deficiency was reported to counteract respiratory inflammation and alveolar damage after bleomycin (BLM)-induced ALI. To explore the molecular mechanisms mediated by Igf1r signaling after BLM challenge, we performed RNA-sequencing in lungs of IGF1R-deficient mice after BLM or saline (SAL) instillation. Transcriptomic analysis identified differentially expressed genes between BLM-challenged and SAL-treated control lungs, detecting biological processes and signaling pathways involved in ALI pathobiology. Igf1r depletion in BLM-challenged mice reversed large part of the transcriptional changes triggered by BLM, counteracting the transcriptomic profile of the inflammatory "cytokine storm". Data mining also identified changes in the expression of gene clusters with key roles in DNA damage, metabolic reprogramming, mitochondrial homeostasis, and epigenetics. Exploration of these functional groups, together with validation studies, provide new insights into the molecular mechanisms underlying the attenuating effect of Igf1r deficiency on ALI. These findings allow a more comprehensive view of IGF1R signaling at the transcriptional level, reinforcing its important role in promoting ALI and postulating it as a global epigenetic regulator in ARDS.
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