Dysregulated lung stroma drives emphysema exacerbation by potentiating resident lymphocytes to suppress an epithelial stem cell reservoir
(2023) In Immunity 56(3). p.10-591- Abstract
Aberrant tissue-immune interactions are the hallmark of diverse chronic lung diseases. Here, we sought to define these interactions in emphysema, a progressive disease characterized by infectious exacerbations and loss of alveolar epithelium. Single-cell analysis of human emphysema lungs revealed the expansion of tissue-resident lymphocytes (TRLs). Murine studies identified a stromal niche for TRLs that expresses Hhip, a disease-variant gene downregulated in emphysema. Stromal-specific deletion of Hhip induced the topographic expansion of TRLs in the lung that was mediated by a hyperactive hedgehog-IL-7 axis. 3D immune-stem cell organoids and animal models of viral exacerbations demonstrated that expanded TRLs suppressed alveolar stem... (More)
Aberrant tissue-immune interactions are the hallmark of diverse chronic lung diseases. Here, we sought to define these interactions in emphysema, a progressive disease characterized by infectious exacerbations and loss of alveolar epithelium. Single-cell analysis of human emphysema lungs revealed the expansion of tissue-resident lymphocytes (TRLs). Murine studies identified a stromal niche for TRLs that expresses Hhip, a disease-variant gene downregulated in emphysema. Stromal-specific deletion of Hhip induced the topographic expansion of TRLs in the lung that was mediated by a hyperactive hedgehog-IL-7 axis. 3D immune-stem cell organoids and animal models of viral exacerbations demonstrated that expanded TRLs suppressed alveolar stem cell growth through interferon gamma (IFNγ). Finally, we uncovered an IFNγ-sensitive subset of human alveolar stem cells that was preferentially lost in emphysema. Thus, we delineate a stromal-lymphocyte-epithelial stem cell axis in the lung that is modified by a disease-variant gene and confers host susceptibility to emphysema.
(Less)
- author
- publishing date
- 2023-03-14
- type
- Contribution to journal
- publication status
- published
- keywords
- Humans, Mice, Animals, Pulmonary Emphysema/genetics, Lung, Emphysema, Lymphocytes, Stem Cells, Pulmonary Disease, Chronic Obstructive
- in
- Immunity
- volume
- 56
- issue
- 3
- pages
- 10 - 591
- publisher
- Cell Press
- external identifiers
-
- scopus:85149875004
- pmid:36822205
- ISSN
- 1074-7613
- DOI
- 10.1016/j.immuni.2023.01.032
- language
- English
- LU publication?
- no
- additional info
- Published by Elsevier Inc.
- id
- 9079162a-c2e5-4c33-ab2e-14c537344549
- date added to LUP
- 2024-05-05 23:58:19
- date last changed
- 2024-10-07 20:03:32
@article{9079162a-c2e5-4c33-ab2e-14c537344549, abstract = {{<p>Aberrant tissue-immune interactions are the hallmark of diverse chronic lung diseases. Here, we sought to define these interactions in emphysema, a progressive disease characterized by infectious exacerbations and loss of alveolar epithelium. Single-cell analysis of human emphysema lungs revealed the expansion of tissue-resident lymphocytes (TRLs). Murine studies identified a stromal niche for TRLs that expresses Hhip, a disease-variant gene downregulated in emphysema. Stromal-specific deletion of Hhip induced the topographic expansion of TRLs in the lung that was mediated by a hyperactive hedgehog-IL-7 axis. 3D immune-stem cell organoids and animal models of viral exacerbations demonstrated that expanded TRLs suppressed alveolar stem cell growth through interferon gamma (IFNγ). Finally, we uncovered an IFNγ-sensitive subset of human alveolar stem cells that was preferentially lost in emphysema. Thus, we delineate a stromal-lymphocyte-epithelial stem cell axis in the lung that is modified by a disease-variant gene and confers host susceptibility to emphysema.</p>}}, author = {{Wang, Chaoqun and Hyams, Ben and Allen, Nancy C and Cautivo, Kelly and Monahan, Kiara and Zhou, Minqi and Dahlgren, Madelene W and Lizama, Carlos O and Matthay, Michael and Wolters, Paul and Molofsky, Ari B and Peng, Tien}}, issn = {{1074-7613}}, keywords = {{Humans; Mice; Animals; Pulmonary Emphysema/genetics; Lung; Emphysema; Lymphocytes; Stem Cells; Pulmonary Disease, Chronic Obstructive}}, language = {{eng}}, month = {{03}}, number = {{3}}, pages = {{10--591}}, publisher = {{Cell Press}}, series = {{Immunity}}, title = {{Dysregulated lung stroma drives emphysema exacerbation by potentiating resident lymphocytes to suppress an epithelial stem cell reservoir}}, url = {{http://dx.doi.org/10.1016/j.immuni.2023.01.032}}, doi = {{10.1016/j.immuni.2023.01.032}}, volume = {{56}}, year = {{2023}}, }