Journal article
A human model of asthma exacerbation reveals transcriptional programs and cell circuits specific to allergic asthma
Science immunology, Vol.8(83), eabq6352
05/12/2023
DOI: 10.1126/sciimmunol.abq6352
PMCID: PMC10440046
PMID: 37146132
Abstract
Asthma is a chronic disease most commonly associated with allergy and type 2 inflammation. However, the mechanisms that link airway inflammation to the structural changes that define asthma are incompletely understood. Using a human model of allergen-induced asthma exacerbation, we compared the lower airway mucosa in allergic asthmatics and allergic non-asthmatic controls using single-cell RNA sequencing. In response to allergen, the asthmatic airway epithelium was highly dynamic and up-regulated genes involved in matrix degradation, mucus metaplasia, and glycolysis while failing to induce injury-repair and antioxidant pathways observed in controls.
-expressing pathogenic T
2 cells were specific to asthmatic airways and were only observed after allergen challenge. Additionally, conventional type 2 dendritic cells (DC2 that express
) and
-expressing monocyte-derived cells (MCs) were uniquely enriched in asthmatics after allergen, with up-regulation of genes that sustain type 2 inflammation and promote pathologic airway remodeling. In contrast, allergic controls were enriched for macrophage-like MCs that up-regulated tissue repair programs after allergen challenge, suggesting that these populations may protect against asthmatic airway remodeling. Cellular interaction analyses revealed a T
2-mononuclear phagocyte-basal cell interactome unique to asthmatics. These pathogenic cellular circuits were characterized by type 2 programming of immune and structural cells and additional pathways that may sustain and amplify type 2 signals, including TNF family signaling, altered cellular metabolism, failure to engage antioxidant responses, and loss of growth factor signaling. Our findings therefore suggest that pathogenic effector circuits and the absence of proresolution programs drive structural airway disease in response to type 2 inflammation.
Details
- Title: Subtitle
- A human model of asthma exacerbation reveals transcriptional programs and cell circuits specific to allergic asthma
- Creators
- Jehan Alladina - Harvard Medical SchoolNeal P Smith - Massachusetts General HospitalTristan Kooistra - Harvard Medical SchoolKamil Slowikowski - Massachusetts General HospitalIsabela J Kernin - Massachusetts General HospitalJacques Deguine - Massachusetts Institute of TechnologyHenry L Keen - University of IowaKasidet Manakongtreecheep - Massachusetts General HospitalJessica Tantivit - Massachusetts General HospitalRod A Rahimi - Harvard Medical SchoolSusan L Sheng - Harvard Medical SchoolNhan D Nguyen - Harvard Medical SchoolAlexis M Haring - Harvard Medical SchoolFrancesca L Giacona - Harvard Medical SchoolLida P Hariri - Massachusetts General HospitalRamnik J Xavier - Harvard Medical SchoolAndrew D Luster - Harvard Medical SchoolAlexandra-Chloé Villani - Massachusetts General HospitalJosalyn L Cho - Division of Pulmonary, Critical Care and Occupational Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USABenjamin D Medoff - Harvard Medical School
- Resource Type
- Journal article
- Publication Details
- Science immunology, Vol.8(83), eabq6352
- DOI
- 10.1126/sciimmunol.abq6352
- PMID
- 37146132
- PMCID
- PMC10440046
- NLM abbreviation
- Sci Immunol
- ISSN
- 2470-9468
- eISSN
- 2470-9468
- Language
- English
- Date published
- 05/12/2023
- Academic Unit
- Pulmonary, Critical Care, and Occupational Medicine; Internal Medicine; Iowa Institute of Human Genetics
- Record Identifier
- 9984400639102771
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