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Heterogeneity of immune cells and their communications unveiled by transcriptome profiling in acute inflammatory lung injury

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE263867 | GEO | 2024/04/17

REPOSITORIES: GEO

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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.

Project description:Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is an inflammatory process of the lungs characterized by increased permeability of the alveolar-capillary membrane with subsequent interstitial/alveolar edema and diffuse alveolar damage. ALI/ARDS can be the results of either direct or indirect lung injury, with pneumonia being the most common direct pulmonary insult and sepsis the most common extra-pulmonary cause. In this study, we employed the murine lipopolysaccharide (LPS)-induced direct and indirect lung injury model to explore the pathogenic mechanisms of pulmonary and extra-pulmonary ARDS, using an unbiased, discovery and quantitative proteomic approach. A total of 1,017 proteins were both identified and quantified in bronchoalveolar lavage fluid (BALF) from control, intratracheal LPS (I.T. LPS, 0.1 mg/kg) and intraperitoneal LPS (I.P. LPS, 5 mg/kg) treated mice. The two LPS groups shared 13 up-regulated and 22 down-regulated proteins compared to the control group. Among them, molecules related to bronchial and type II alveolar epithelial cell functions including cell adhesion molecule 1 and surfactant protein B were reduced, whereas lactotransferrin and resistin like alpha involved in lung innate immunity were upregulated in both LPS groups. Proteomic profiling also identified significant differences in BALF proteins between I.T. and I.P. LPS groups. Ingenuity pathway analysis revealed that acute-phase response signaling was activated by both I.T. and I.P. LPS, however, the magnitude of activation is much greater in I.T. LPS group compared to I.P. LPS group. Intriguingly, two canonical signaling pathways, liver X receptor/retinoid X receptor activation and the production of nitric oxide and reactive oxygen species in macrophages, were activated by I.T. LPS but suppressed by I.P. LPS. In addition, CXCL15 (also known as lungkine) was also up-regulated by I.T LPS but down-regulated by I.P. LPS. In conclusion, our quantitative discovery-based proteomic approach identified commonalities as well as significant differences in BALF protein expression profiles in LPS-induced direct and indirect lung injury, and importantly, LPS-induced indirect lung injury results in suppression of select components of lung innate immunity, which could contribute to the so-called “immunoparalysis” in sepsis patients.

Project description: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. 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. 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). 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. The Cohort is utilized in the following dbGaP sub-studies. 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>

Project description:Background: COVID-19 and sepsis represent formidable public health challenges, characterized by incompletely elucidated molecular mechanisms. Elucidating the interplay between COVID-19 and sepsis, particularly in geriatric patients suffering from sepsis-induced acute respiratory distress syndrome (ARDS), is of paramount importance for identifying potential therapeutic interventions to mitigate hospitalization and mortality risks.We employed bioinformatics and systems biology approaches to identify hub genes, shared pathways, molecular biomarkers, and candidate therapeutics for managing COVID-19, sepsis, and sepsis-induced ARDS. We corroborated these hub genes utilizing murine sepsis-ARDS models and blood samples derived from geriatric patients afflicted by sepsis-induced ARDS.Results: Our investigation revealed 189 differentially expressed genes (DEGs) shared among COVID-19 and sepsis datasets. We constructed a protein-protein interaction network, unearthing pivotal hub genes and modules. Notably, nine hub genes displayed significant alterations and correlations with critical inflammatory mediators of pulmonary injury in murine septic lungs. Simultaneously, 12 displayed significant changes and correlations with a neutrophil-recruiting chemokine in geriatric patients with sepsis-induced ARDS. Of these, six hub genes (CD247, CD2, CD40LG, KLRB1, LCN2, RETN) showed significant alterations across COVID-19, sepsis, and geriatric sepsis-induced ARDS. Our single-cell RNA sequencing analysis of hub genes across 3 diverse immune cell types furnished insights into disease pathogenesis. Functional analysis underscored the interconnection between sepsis/sepsis-ARDS and COVID-19, enabling us to pinpoint potential therapeutic targets, transcription factor-gene interactions, DEG-microRNA co-regulatory networks, and prospective drug and chemical compound interactions involving hub genes.Our investigation offers potential therapeutic targets/biomarkers, sheds light on the immune response in geriatric patients with sepsis-induced ARDS, emphasizes the association between sepsis/sepsis-ARDS and COVID-19, and proposes novel avenues for targeted therapies.

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Heterogeneity of immune cells and their communications unveiled by transcriptome profiling in acute inflammatory lung injury

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