Single-cell transcriptomic analysis reveals the immune landscape of lung in steroid-resistant asthma exacerbation

Exaggerated airway hyperresponsiveness and inflammation are hallmarks of asthma, and lipopolysaccharide (LPS) exposure is linked to the severity of the disease and steroid resistance. To investigate the mechanisms underlying asthma exacerbation, we established a mouse model of LPS-induced steroid-re...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 118; no. 2; pp. 1 - 11
Main Authors Wang, Lingli, Netto, Keilah G., Zhou, Lujia, Liu, Xiaojie, Wang, Ming, Zhang, Guojun, Foster, Paul S., Li, Fuguang, Yang, Ming
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 12.01.2021
Subjects
Animals
Asthma - immunology
Biological Sciences
Disease Progression
Interleukin-13 - metabolism
Interleukin-4 - metabolism
Leukocytes - metabolism
Lipopolysaccharides
Lung - immunology
Mice
Mice, Inbred BALB C
Mononuclear Phagocyte System - metabolism
Pyroglyphidae - immunology
Single-Cell Analysis
Transcriptome
single-cell RNA sequencing
pathway analysis
asthma exacerbation
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Summary:Exaggerated airway hyperresponsiveness and inflammation are hallmarks of asthma, and lipopolysaccharide (LPS) exposure is linked to the severity of the disease and steroid resistance. To investigate the mechanisms underlying asthma exacerbation, we established a mouse model of LPS-induced steroid-resistant exacerbation on the background of house dust mite (HDM)-induced asthma to profile the immune cells in lung by using single-cell RNA deep sequencing. Twenty immune subsets were identified by their molecular and functional properties. Specific cell clusters of basophils, type 2 innate lymphoid cells (ILC2), and CD8⁺ memory T cells were the predominant sources of interleukin (IL)-4 and IL-13 transcripts whose expressions were dexamethasone resistant. Production of IL-13 by these cells was validated by IL-13-reporter mice. Neutralization of IL-13 abolished HDM/LPS-induced airway hyperresponsiveness, airway inflammation, and decreased mucus hypersecretion. Furthermore, using Ingenuity Pathway Analysis systems, we identified canonical pathways and upstream regulators that regulate the activation of basophils, ILC2, and CD8⁺ memory T cells. Our study provides mechanistic insights and an important reference resource for further understanding of the immune landscape during asthma exacerbation.
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Edited by Ariel Munitz, Tel Aviv University, Tel Aviv, Israel, and accepted by Editorial Board Member Ruslan Medzhitov November 27, 2020 (received for review April 15, 2020)
Author contributions: F.G.L. and M.Y. designed research; L.L.W., K.G.N., L.J.Z., X.J.L., and M.W. performed research; G.J.Z. contributed new reagents/analytic tools; L.L.W., K.G.N., P.S.F., F.G.L., and M.Y. analyzed data; and F.G.L. and M.Y. wrote the paper.
1L.L.W. and K.G.N. contributed equally to this work.
2F.G.L. and M.Y. contributed equally to this work.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2005590118