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Increased mitochondrial metabolism in neutrophils revealed by single-cell RNA sequencing (scRNAseq) of bronchoalveolar lavage fluid (BALF) predicts remission in a fatal case of neutrophilic asthma

ABSTRACT: We present a case of lethal neutrophilic asthma, in which the patient required mechanical ventilation due to hypoxia and hypercapnia. After receiving high-dose steroid treatment, the patient eventually recovered and was successfully weaned off mechanical ventilation. To investigate the underlying mechanisms, we performed single-cell RNA sequencing (scRNAseq) analysis on the patient's bronchoalveolar lavage fluid (BALF) both before and during the remission phase. During the remission phase, we discovered a cluster of hybrid recovery-specific neutrophils (rs-Neus) that exhibited significantly higher levels of oxidative phosphorylation (OxPhos) and Tricarboxylic Acid Cycle (TCA) compared to pathological neutrophils (pNeus). Moreover, we observed a significant decrease in the inflammatory response in rs-Neus, which was found to be negatively correlated with their mitochondrial metabolic activity. Pathway analysis suggested that the hypoxia signaling pathway played a key role in the observed metabolic changes. Our fins highlight the changes in the metabolic landscape of neutrophils in BALF during the development of severe neutrophilic asthma. Furthermore, our study suggests that neutrophil mitochondrial metabolism may serve as an essential indicator of remission and underscores the potential of targeting neutrophil metabolism as a therapeutic strategy for severe neutrophilic asthma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE227744 | GEO | 2023/03/23

REPOSITORIES: GEO

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Airborne particulate matter from goat farm increases acute allergic airway responses in mice increases acute allergic airway responses in mice

Project description:Background: Inhalation exposure to biological particulate matter (BioPM) from livestock farms may provoke exacerbations in subjects suffering from allergy and asthma. The aim of this study was to use a murine model of allergic asthma to determine the effect of BioPM derived from goat farm on airway allergic responses Methods: Fine (< 2.5 μm) BioPM was collected from an indoor goat stable. Female BALB/c mice were ovalbumin (OVA) sensitized and challenged with OVA or saline as control. The OVA and saline groups were divided in sub-groups and exposed intranasally to different concentrations (0, 0.9, 3, or 9 μg) of goat farm BioPM. Bronchoalveolar lavage fluid (BALF), blood and lung tissues were collected. Results: In saline-challenged mice, goat farm BioPM alone induced a dose-dependent increase in neutrophils in BALF and induced production of macrophage inflammatory protein-3a). In OVA-challenged mice, BioPM significantly enhanced 1) inflammatory cells in BALF, 2) OVA-specific Immunoglobulin (Ig)G1, 3) interleukin-23 production, 4) airway mucus secretion-specific gene expression. RNAseq analysis of lungs indicates that neutrophil chemotaxis and oxidation-reduction processes were the representative genomic pathways in saline and OVA-challenged mice, respectively. Conclusions: A single exposure to goat farm BioPM enhanced airway inflammation in both saline and OVA-challenged allergic mice, with neutrophilic response as Th17 disorder and eosinophilic response as Th2 disorder indicative of the severity of allergic responses. Identification of the mode of action by which farm PM interacts with airway allergic pathways will be useful to design potential therapeutic approaches.

2020-08-01 | GSE148240 | GEO

Distinct Immune Cell Functional Phenotypes in Sepsis Patients Correlates with Disease Severity

Project description:Sepsis is a highly heterogeneous syndrome that impacts immune function and response to infection. To develop targeted therapeutics, immunophenotyping is needed to identify distinct immune cell functional phenotypes. Employing organ-on-chip for neutrophil functional analysis, we identified three distinct sepsis neutrophil phenotypes based on adhesion and migration patterns across human lung endothelial cells in response to cytokine activation (cytomix, TNF/IL-1β/IFNγ). The phenotypes were categorized as: a Hyperimmune phenotype characterized by enhanced cytomix-induced neutrophil adherence and migration, a Hypoimmune phenotype that was unresponsive to cytomix treatment, and a Hybrid phenotype with increased adherence but blunted migration in response to stimulation. Proteomic analysis identified both unique and shared proteins between the three phenotypes as compared to healthy controls. Proteins associated with neutrophil adherence were significantly upregulated in the Hyperimmune and Hybrid neutrophils, while the Hypoimmune group showed significant downregulation of these proteins. Clinically, the Hypoimmune group had significantly fewer patients requiring mechanical ventilation (29%) compared to the Hyperimmune group (70%). The Hypoimmune group and Hybrid group had significantly shorter ICU length of stay (LOS) than the Hyperimmune group. The Hypoimmune group also showed a trend for a lower mortality rate (35.7%) compared to the Hyperimmune group (50%). Thus, we identified associations between neutrophil phenotypes and important clinical outcomes, such as mechanical ventilation requirements, ICU LOS, and possibly mortality. Classification of sepsis patient phenotypes with diverse functional neutrophil responses and proteomic signatures can help distinguish patients who would benefit from specific treatments, such as immunosuppressive therapies and those who may be negatively impacted.

2024-03-05 | PXD041007 | Pride

Evaluation of pulmonary complications during laparoscopic surgery in patients with protective mechanical ventilation combined deep neuromuscular block

Project description:Interventions: Group 1:protective mechanical ventilation combined deep neuromuscular block and low pneumoperitoneum pressure ;Group 2:routine mechanical ventilation combined with routine neuromuscular block and pneumoperitoneum pressure Primary outcome(s): Neutrophil Elastase, NE;Modified Clinical Pulmonary Infection Score, mCPIS;surgical rating scale, SRS Study Design: Parallel

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ATF3 is a novel regulator of mouse neutrophil migration.

Project description:Expression of the activating transcription factor 3 (ATF3) gene is induced by Toll-like receptor (TLR) signaling. In turn, ATF3 protein inhibits the expression of various TLR-driven pro-inflammatory genes. Given its counter-regulatory role in diverse innate immune responses, we defined the effects of ATF3 on neutrophilic airway inflammation in mice. ATF3 deletion was associated with increased lipopolysaccharide (LPS)-driven airway epithelia production of CXCL1, but not CXCL2, findings concordant with a consensus ATF3-binding site identified solely in the Cxcl1 promoter. Unexpectedly, ATF3-deficient mice did not exhibit increased airway neutrophilia after LPS challenge. Bone marrow chimeras revealed a specific reduction in ATF3-/- neutrophil recruitment to wild type lungs. In vitro, ATF3-/- neutrophils exhibited a profound chemotaxis defect. Global gene expression analysis identified ablated Tiam2 expression in ATF3-/- neutrophils. TIAM2 regulates cellular motility by activating Rac1-mediated focal adhesion disassembly. Notably, ATF3-/- and ATF3-sufficient TIAM2 knockdown neutrophils, both lacking TIAM2, exhibited increased focal complex area, along with excessive CD11b-mediated F-actin polymerization. Together, our data describe a dichotomous role for ATF3-mediated regulation of neutrophilic responses: inhibition of neutrophil chemokine production, but promotion of neutrophil chemotaxis. Ly6G+ neutrophils were purified by magnetic beads from WT or ATF3 KO bone marrow and RNA was immediately isolated for global gene expression using microarrays.

2014-04-05 | E-GEOD-53973 | biostudies-arrayexpress

¬The EGFR/ErbB inhibitor neratinib promotes apoptosis and clearance by airway macrophages

Project description:Dysregulated neutrophilic inflammation can be highly destructive in chronic inflammatory diseases due to prolonged neutrophil lifespan and continual release of histotoxic mediators in inflamed tissues. Inducing neutrophil apoptosis, an immunologically silent form of cell death, may be beneficial in these diseases, provided that the apoptotic neutrophils are efficiently cleared from the tissue. Our previous research identified ErbB inhibitors as able to induce neutrophil apoptosis and reduce neutrophilic inflammation both in vitro and in vivo (Rahman et al. 2019). Here we expand on that work using a clinical ErbB inhibitor, neratinib, which has the potential to be repurposed in inflammatory diseases. We show that neratinib reduces neutrophilic migration to an inflammatory site in zebrafish larvae. Neratinib upregulates efferocytosis and reduces the number of dead neutrophils in mouse models of acute, but not chronic, lung injury, suggesting the drug may have therapeutic benefits in acute inflammatory settings. Phosphoproteomics analysis of human neutrophils shows that neratinib modifies the phosphorylation of proteins regulating apoptosis, migration and efferocytosis. This work identifies a potential efficacious mechanism for neratinib in acute lung inflammation by upregulating the clearance of dead neutrophils, and examination of the neutrophil phosphoproteome gives insight into the mechanisms by which this may be occurring.

2022-07-22 | PXD035125 | Pride

BALF single-cell landscape in CARDS and non-ARDS patients at two time points

Project description:In this study, single-cell sequencing of the BALF of CARDS patients yielded the following results: (1) IL1B+ neutrophils were significantly increased in the BALF of CARDS patients with exacerbated disease, which was associated with poor prognosis of CARDS patients, and this type of neutrophils underwent fatty acid metabolism reprogramming in comparison with other types of neutrophils, which may be related to their high-inflammatory response. (2) IL1B+ neutrophils promoted TNF secretion from hyperinflammatory type M1 macrophages through a caspase-dependent pathway, suggesting that neutrophil-macrophage interactions play an important role in the mechanism of CARDS development.

2024-05-15 | GSE240580 | GEO

Deficiency of IFT20 in CD4+ T cell alleviates protease-induced neutrophilic asthma-like inflammation

Project description:Many neutrophilic asthma patients do not respond to current medications, highlighting the need for novel therapeutic targets. Here, we investigated the role of intraflagellar transport (IFT) complex protein IFT20 in neutrophilic asthma. Mice lacking CD4+ T cell-specific IFT20 displayed reduced protease-induced neutrophilic asthma inflammation. Thus, IFT20 may represent a promising therapeutic target for treatment of patients with neutrophilic asthma.

2022-07-31 | GSE179622 | GEO

Single-cell transcriptional profiles of BM, PB and lung neutrophils from naïve (C57BL/6J), AT3, and AT3-gcsf tumor-bearing mice

Project description:To determine the effect of tumor-bearing vs. host neutrophilic inflammation on reinforcement of lung neutrophil-specific immunosuppressive function, we performed single-cell RNA sequencing (scRNA-seq) on BM, PB and lung neutrophils isolated from naïve (C57BL/6J), AT3, and AT3-gcsf tumor-bearing mice.

2022-12-12 | GSE217595 | GEO

ATF3 is a novel regulator of mouse neutrophil migration.

2014-04-05 | GSE53973 | GEO

A sputum gene expression signature of six biomarkers identifies asthma inflammatory phenotype and steroid responsiveness

Project description:This study identifies differentially expression genes in the sputum of people with eosinophilic, neutrophilic and paucigranulocytic asthma. A selection of markers identified using this microarray were further validated using qPCR on a wider sample set. Gene expression profiles were generated from induced sputum samples from 47 asthma patients and were grouped by the inflammatory phenotype assigned using sputum cell counts into neutrophilic asthma (n=12), eosinophilic asthma (n=17) and paucigranulocytic asthma (n=18). RNA was extracted, amplified and hybridised to Illumina Sentrix HumanRef-8 Version 2 Expression BeadChips, and genes that were differentially expressed between asthma inflammatory phenotypes were compared.

2014-03-25 | E-GEOD-45111 | biostudies-arrayexpress

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