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Single-Cell Sequencing Reveals Immune Contributors to Exacerbated Asthma in Mouse Model

NEW YORK – A team from China and Australia used single-cell transcriptomics to characterize the immune cells involved in asthma responses in the lung in a mouse model of the chronic inflammatory disease.

"Our study provides mechanistic insights and an important reference resource for further understanding of the immune landscape during asthma exacerbation," co-first and co-corresponding author Lingli Wang, a medical sciences and immunology researcher at Zhengzhou University, and her colleagues wrote in the Proceedings of the National Academy of Sciences on Monday.

"Asthma exacerbation is not prevented by standard corticosteroid-based therapy and is the major burden in terms of morbidity, mortality, and health care costs associated with asthma," they added.

For their study, the researchers used 10x Genomics and Illumina platforms to perform deep, droplet-based single-cell RNA sequencing on more than 5,800 immune cells originating in the lungs of six mice with steroid-resistant asthma that had been exposed to house dust mites and bacterial lipopolysaccharides that aggravated the condition. They compared those transcriptome profiles with those in thousands of immune cells from the lungs of control mice treated with saline or from lung samples in mice with aggravated asthma in the absence of corticosteroid treatment, identifying 20 main immune cell clusters contributing to the condition.

"We found multicellular signaling pathways closely associated with disease progression during the exacerbation," the authors reported, adding that the study's findings "provide important insights into how the immune landscape in lung during asthma exacerbation can shape the progress of disease."

In dust mite-exposed, dexamethasone steroid-treated mice with asthma, for example, the team saw a jump in interleukin-4 (IL-4) and interleukin-13 (IL-13) cytokine production by CD8+ memory T cells, type 2 innate lymphoid (ILC2) immune cells, and basophils when asthma was exacerbated — findings that were subsequently verified with experiments done in mice with a fluorescently tagged reporter version of the IL-13 cytokine.

In contrast, the investigators found that they could dial back symptoms such as airway inflammation, hyper-responsiveness by airway tissue, and higher-than-usual mucus secretion in the mouse models exposed to dust mite and lipopolysaccharide triggers by neutralizing the IL-13 with an injected antibody targeting the cytokine.

For their follow-up analyses, the researchers used pathway enrichment analyses to explore the processes and regulatory features that influence activity by the IL-13-producing ILC2, CD8+ memory T cells, and basophils flagged by the single-cell transcriptomic data.

"Our single-cell profiling of lung immune cells adds to the understanding of the cellular makeup of the lung organ and provides a vital information resource of the immune cellular network in lung during asthma exacerbation and steroid resistance," the authors wrote, concluding that cellular and signaling pathway details detected in the mouse asthma model provide "a benchmark for the development of cell-targeted therapies to treat and prevent asthma exacerbations."

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