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Single cell transcriptional profiling of monocytes from asthma patients show a predisposition for an inflammatory response

ABSTRACT: Background: Asthma is the most common chronic lung disorder among children and young adults worldwide. Standard of care therapies are only partially effective and have side effects. Despite highly effective new biologic therapies, ~10% of patients continue to be poorly controlled. Methods. We isolated monocytes from peripheral blood obtained from an asthma patient who received an infusion of interferon γ-activated mesenchymal stromal cells (γMSCs), before and at 15 and 35 days after the infusion. We similarly isolated blood monocytes from otherwise healthy subjects with asthma and healthy controls for comparison. We interrogated the monocyte samples with single cell RNA sequencing followed by data analysis using the Seurat pipeline. Findings: A single infusion of γMSCs induced a profound change in circulating monocyte gene expression, including reduction of HLA Class I expression and reduction of gene expression associated with type 1 and type 3 interferon signaling. Further examination of CD14+ and CD16+ monocytes from asthma patients revealed higher expression of proinflammatory genes compared to healthy controls, most notably increased expression of interferon response pathway genes. Within the asthma patients, several viral and interferon response pathways were significantly enriched in severe versus mild asthma. Interpretation: Circulating monocytes from asthma patients may be intrinsically programmed with a dysregulated interferon response. Monocyte directed therapy may be beneficial, especially for patients who are poorly controlled on currently available therapy. Finally, our data suggest that additional studies of γMSC therapy for patients with poorly controlled asthma is warranted.

ORGANISM(S): Homo sapiens

PROVIDER: GSE288147 | GEO | 2025/09/01

REPOSITORIES: GEO

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Project description:Background: Around 5% of children with asthma suffer from chronic symptoms and/or severe exacerbations despite extensive treatment. The causes of severe therapy-resistant childhood asthma are poorly understood. Objectives: To define global patterns of gene expression in severe therapy-resistant vs. controlled asthma and healthy controls. Methods: Children with severe, therapy-resistant (SA, n=20) and controlled asthma (CA, n=20) were identified from a Swedish nation-wide study including extensive clinical and immunological characterisation. In addition, healthy controls were recruited (Ctrl, n=19). White blood cells were isolated and the global transcriptome profile was characterised using the Affymetrix Human Gene ST 1.0 chip. Results: 1378 genes were differentially expressed in one or several of the CA vs. Ctrl, SA vs. CA or SA vs. Ctrl contrasts. A large number could uniquely differentiate the SA group from the CA (n=351 genes) and Ctrl (n=315) groups, whereas fewer genes differentiated the CA from the Ctrl group (n=149). Several non-coding RNAs were found up-regulated in SA compared to CA or Ctrl. Three significantly enriched KEGG pathways were represented; bitter taste transduction, TAS2Rs (up-regulated mostly in SA), natural killer cell mediated cytotoxicity (up-regulated in CA) and N-Glycan biosynthesis (down-regulated in SA). An unsupervised hierarchical clustering of the 1378 genes could crudely separate the SA, CA and Ctrl individuals. Conclusion: Our data indicate a separation in gene expression patterns between children with severe, therapy-resistant asthma and controlled persistent asthma, and suggest novel pathways characterizing the severe therapy-resistant asthma phenotype. The transcriptomes of 59 subjects were assayed on the Affymetrix Human Gene ST 1.0 expression array. All samples passed pre-hybridisation quality control. After pre-processing and quality control of the post-hybridised arrays, five samples were regarded as outliers and removed (ctrl 510, MA 248, SA 141, SA 261, SA 41). The remaining sample set of 17 severe asthmatics (SA), 19 mild asthmatics (MA) and 18 controls (ctrl) were used for down-stream analysis.

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Single cell transcriptional profiling of monocytes from asthma patients show a predisposition for an inflammatory response

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