| Autor: |
Alladina, Jehan, Smith, Neal P., Kooistra, Tristan, Slowikowski, Kamil, Kernin, Isabela J., Deguine, Jacques, Keen, Henry L., Manakongtreecheep, Kasidet, Tantivit, Jessica, Rahimi, Rod A., Sheng, Susan L., Nguyen, Nhan D., Haring, Alexis M., Giacona, Francesca L., Hariri, Lida P., Xavier, Ramnik J., Luster, Andrew D., Villani, Alexandra-Chloé, Cho, Josalyn L., Medoff, Benjamin D. |
| Zdroj: |
Science Immunology; 2023, Vol. 8 Issue 83, p1-19, 19p |
| Abstrakt: |
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. IL9-expressing pathogenic TH2 cells were specific to asthmatic airways and were only observed after allergen challenge. Additionally, conventional type 2 dendritic cells (DC2 that express CD1C) and CCR2-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 TH2–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. Off-kilter asthmatic airways: A subset of individuals with allergies also have asthma and airway hyperresponsiveness. Uncertainty remains about what cellular and molecular events in the airway after allergen exposure differentiate patients with allergic asthma from those who just have allergies. Alladina and Smith et al. performed bronchoscopic experimental allergen challenges in lung segments of house dust mite- or cat-allergic individuals with and without asthma. Analysis of cellular and gene-expression changes in cells collected from the airways one day post-challenge revealed dysregulated cellular interactions in asthmatics involving both immune and structural cells that preferentially amplified inflammation rather than promoting repair. The findings provide fresh insights into the pathogenic cellular circuits specifically associated with asthmatic lung disease. —IRW [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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