Human airway mast cells proliferate and acquire distinct inflammation-driven phenotypes during type 2 inflammation
- 1 February 2021
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Immunology
- Vol. 6 (56)
- https://doi.org/10.1126/sciimmunol.abb7221
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 CD38(high)CD117(hi)(gh) MCs that is markedly expanded during T2 inflammation. These CD38(high)CD117(hi)(gh) MCs exhibit an intermediate phenotype relative to the expanded MCT and MCTc subsets. CD38(high)CD117(high) 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.Funding Information
- National Institutes of Health (R37AI052353)
- National Institutes of Health (R01AI136041)
- National Institutes of Health (R01AI130109)
- National Institutes of Health (R01HL136209)
- National Institutes of Health (U19AI095219)
- National Institutes of Health (R01HL120952)
- Bill and Melinda Gates Foundation
- Alfred P. Sloan Foundation
- National Institutes of Health (U24AI118672)
- National Institutes of Health (T32AI007306)
- National Institutes of Health (R01AI134989)
- National Institutes of Health (U19AI095219)
- National Institutes of Health (U19AI070535)
- National Institute of Allergy and Infectious Diseases (K22AI146281)
- Damon Runyon Cancer Research Foundation (DRG-2274-16)
- National Institutes of Health (U19AI070535)
- National Institutes of Health (R01HL128241)
- National Institutes of Health (U19AI095219)
- Searle Scholars Program
- Beckman Young Investigator Program
- Pew-Stewart Scholars Program for Cancer Research
- Steven and Judy Kaye Young Innovators Award
- European Commission Directorate-General for Research and Innovation (grant agreement no. 874656 (discovAIR))
- Food Allergy Science Initiative
- AGA Research Foundation’s AGA-Takeda Pharmaceuticals Research Scholar Award in IBD (AGA2020-13-01)
- Richard and Susan Smith Family Foundation
- New York Stem Cell Foundation
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