Single-cell transcriptomic analysis reveals key immune cell phenotypes in the lungs of patients with asthma exacerbation - 04/03/21

Doi : 10.1016/j.jaci.2020.09.032

Hui Li, MMED ^a,^{∗
These authors contributed equally to this work.}, Huaqi Wang, PhD ^a,^{∗
These authors contributed equally to this work.}, Leon Sokulsky, PhD ^b, Shaoxia Liu, PhD ^a, Rui Yang, PhD ^a, Xiaojie Liu, BMED ^c, Lujia Zhou, BMED ^c, Juan Li, PhD ^a, Chun Huang, MMED ^a, Fangfang Li, MMED ^a, Xu Lei, MMED ^a, Hongxia Jia, MMED ^a, Jiuling Cheng, MMED ^a, Fuguang Li, PhD ^c, Ming Yang, PhD ^b,^c,^⁎,^{^{‡
These authors contributed equally to this work.}} , Guojun Zhang, PhD ^a,^⁎,^{^{‡
These authors contributed equally to this work.}}
^a Department of Respiratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
^b Priority Research Centre for Healthy Lungs, School of Biomedical Sciences and Pharmacy, Faculty of Health and Hunter Medical Research Institute, University of Newcastle, Callaghan, Australia
^c Academy of Medical Sciences and Department of Immunology, College of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China

^∗Corresponding author: Guojun Zhang, PhD, Department of Respiratory Medicine, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, Henan 450052, P.R. China.Department of Respiratory MedicineThe First Affiliated Hospital of Zhengzhou UniversityNo. 1Jianshe East RoadZhengzhouHenan450052P.R. China^∗∗Ming Yang, PhD, Academy of Medical Sciences, Zhengzhou University and Priority Research Centre for Healthy Lungs, School of Biomedical Sciences and Pharmacy, Faculty of Health and Hunter Medical Research Institute, Lot 1 Kookaburra Circuit, New Lambton Heights, NSW 2305, Australia.Academy of Medical SciencesZhengzhou University and Priority Research Centre for Healthy LungsSchool of Biomedical Sciences and PharmacyFaculty of Health and Hunter Medical Research InstituteLot 1 Kookaburra CircuitNew Lambton HeightsNSW2305Australia

Abstract

Background

Asthma exacerbations are associated with heightened asthma symptoms, which can result in hospitalization in severe cases. However, the molecular immunologic processes that determine the course of an exacerbation remain poorly understood, impeding the progression of development of effective therapies.

Objective

Our aim was to identify candidate genes that are strongly associated with asthma exacerbation at a cellular level.

Methods

Subjects with asthma exacerbation and healthy control subjects were recruited, and bronchoalveolar lavage fluid was isolated from these subjects via bronchoscopy. Cells were isolated through fluorescence-activated cell sorting, and single-cell RNA sequencing was performed on enriched cell populations.

Results

We showed that the levels of monocytes, CD8⁺ T cells, and macrophages are significantly elevated in the bronchoalveolar lavage fluid of patients. A set of cytokines and intracellular transduction regulators are associated with asthma exacerbations and are shared across multiple cell clusters, forming a complicated molecular framework. An additional group of core exacerbation-associated modules is activated, including eukaryotic initiation factor 2 signaling, ephrin receptor signaling, and C-X-C chemokine receptor type 4 signaling in the subpopulations of CD8⁺ T cells (C1-a) and monocyte clusters (C7 clusters), which are associated with infection.

Conclusion

Our study identified a significant number of severe asthma–associated genes that are differentially expressed by multiple cell clusters.

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Key words : Asthma, single-cell RNA-sequencing, T lymphocytes, B lymphocytes, monocytes, neutrophils, macrophages, cytokines, chemokines

Abbreviations used : AHR, BALF, FACS, GMP, IPA, NK, SARP, scRNA-seq, TLR, tSNE, U-BIOPRED

Plan

Methods

Study design and eligibility

Healthy subjects

Bronchoscopy procedure

FACS sorting

Single-cell gene expression

Bioinformatic analysis of scRNA-seq data

Statistical analysis

Results

Characterization of the participants

scRNA-seq on lung immune cells identifies multiple clusters of immune cells

Asthma exacerbations result in distinct cell clusters in BALF

Intracellular signaling activity analyses

Expression of SARP and U-BIOPRED genes

Gene network analyses

Discussion

	Supported by a University-Hospital Joint Fostering Fund of Zhengzhou University (grant 23230016) and China National Natural Science Foundation Project Grants (81874042 and 81970030).
	Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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Vol 147 - N° 3

P. 941-954 - mars 2021 Retour au numéro

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Single-cell transcriptomic analysis reveals key immune cell phenotypes in the lungs of patients with asthma exacerbation - 04/03/21

Abstract

Background

Objective

Methods

Results

Conclusion

Plan

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