Human airway mast cells proliferate and acquire distinct inflammation-driven phenotypes during type 2 inflammation
Name
nihms-1726052.pdf
Description
Accepted version
Size
3.1 MB
Format
Adobe PDF
Checksum (MD5)
fc113bcd53894bddde5ca6f3cb28a377
Author(s)
Dwyer, Daniel F
Ordovas-Montanes, Jose
Allon, Samuel J
Buchheit, Kathleen M
Vukovic, Marko
Derakhshan, Tahereh
Feng, Chunli
Lai, Juying
Hughes, Travis K
Nyquist, Sarah K
Date Issued
2021
Journal
Science immunology
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Dwyer, Daniel F, Ordovas-Montanes, Jose, Allon, Samuel J, Buchheit, Kathleen M, Vukovic, Marko et al. 2021. "Human airway mast cells proliferate and acquire distinct inflammation-driven phenotypes during type 2 inflammation." Science immunology, 6 (56).
Version
Final published version
Abstract
Mast cells (MCs) play a pathobiologic role in type 2 (T2) allergic inflammatory diseases of the airway, including asthma and chronic rhinosinusitis with nasal polyposis (CRSwNP). Distinct MC subsets infiltrate the airway mucosa in T2 disease, including subepithelial MCs expressing the proteases tryptase and chymase (MCTC) and epithelial MCs expressing tryptase without chymase (MCT). However, mechanisms underlying MC expansion and the transcriptional programs underlying their heterogeneity are poorly understood. Here, we use flow cytometry and single-cell RNA-sequencing (scRNA-seq) to conduct a comprehensive analysis of human MC hyperplasia in CRSwNP, a T2 cytokine-mediated inflammatory disease. We link discrete cell surface phenotypes to the distinct transcriptomes of CRSwNP MCT and MCTC, which represent polarized ends of a transcriptional gradient of nasal polyp MCs. We find a subepithelial population of CD38highCD117high MCs that is markedly expanded during T2 inflammation. These CD38highCD117high MCs exhibit an intermediate phenotype relative to the expanded MCT and MCTC subsets. CD38highCD117high MCs are distinct from circulating MC progenitors and are enriched for proliferation, which is markedly increased in CRSwNP patients with aspirin-exacerbated respiratory disease, a severe disease subset characterized by increased MC burden and elevated MC activation. We observe that MCs expressing a polyp MCT-like effector program are also found within the lung during fibrotic diseases and asthma, and further identify marked differences between MCTC in nasal polyps and skin. These results indicate that MCs display distinct inflammation-associated effector programs and suggest that in situ MC proliferation is a major component of MC hyperplasia in human T2 inflammation.
MIT Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Massachusetts Institute of Technology. Department of Chemistry
Koch Institute for Integrative Cancer Research at MIT
Ragon Institute of MGH, MIT and Harvard
Massachusetts Institute of Technology. Computational and Systems Biology Program
Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory
Massachusetts Institute of Technology. Department of Mathematics
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1126/SCIIMMUNOL.ABB7221
