Dysregulated lung stroma drives emphysema exacerbation by potentiating resident lymphocytes to suppress an epithelial stem cell reservoir
Wang, Chaoqun ; Hyams, Ben ; Allen, Nancy C ; Cautivo, Kelly ; Monahan, Kiara ; Zhou, Minqi ; Dahlgren, Madelene W LU
; Lizama, Carlos O
; Matthay, Michael
and Wolters, Paul
, et al.
(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
- Wang, Chaoqun
; Hyams, Ben
; Allen, Nancy C
; Cautivo, Kelly
; Monahan, Kiara
; Zhou, Minqi
; Dahlgren, Madelene W
LU
; Lizama, Carlos O
; Matthay, Michael
and Wolters, Paul
, et al. (More)
- Wang, Chaoqun
; Hyams, Ben
; Allen, Nancy C
; Cautivo, Kelly
; Monahan, Kiara
; Zhou, Minqi
; Dahlgren, Madelene W
LU
; Lizama, Carlos O
; Matthay, Michael
; Wolters, Paul
; Molofsky, Ari B
and Peng, Tien
(Less)
- 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
- 2024-05-06 09:24:04
@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}},
}