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Dysregulated lung stroma drives emphysema exacerbation by potentiating resident lymphocytes to suppress an epithelial stem cell reservoir.
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- Author(s): Wang C;Wang C;Wang C; Hyams B; Hyams B; Hyams B; Allen NC; Allen NC; Allen NC; Cautivo K; Cautivo K; Cautivo K; Monahan K; Monahan K; Monahan K; Zhou M; Zhou M; Zhou M; Dahlgren MW; Dahlgren MW; Dahlgren MW; Lizama CO; Lizama CO; Matthay M; Matthay M; Wolters P; Wolters P; Molofsky AB; Molofsky AB; Molofsky AB; Peng T; Peng T; Peng T; Peng T
- Source:
Immunity [Immunity] 2023 Mar 14; Vol. 56 (3), pp. 576-591.e10. Date of Electronic Publication: 2023 Feb 22.- Publication Type:
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't- Language:
English - Source:
- Additional Information
- Source: Publisher: Cell Press Country of Publication: United States NLM ID: 9432918 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4180 (Electronic) Linking ISSN: 10747613 NLM ISO Abbreviation: Immunity Subsets: MEDLINE
- Publication Information: Publication: Cambridge, MA : Cell Press
Original Publication: Cambridge, Mass. : Cell Press, c1994- - Subject Terms:
- 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 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.
Competing Interests: Declaration of interests The authors declare no competing interests.
(Published by Elsevier Inc.) - Comments: Comment in: Immunity. 2023 Mar 14;56(3):465-467. (PMID: 36921570)
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Am J Respir Crit Care Med. 2017 Feb 1;195(3):324-330. (PMID: 27556408) - Grant Information: P30 DK063720 United States DK NIDDK NIH HHS; R01 HL142552 United States HL NHLBI NIH HHS; R01 HL142701 United States HL NHLBI NIH HHS; R01 HL155622 United States HL NHLBI NIH HHS
- Contributed Indexing: Keywords: COPD; HHIP; adventitia; alveolar stem cell; emphysema; fibroblast; hedgehog; interferon gamma; respiratory viral infection; tissue-resident lymphocytes
- Publication Date: Date Created: 20230223 Date Completed: 20230320 Latest Revision: 20240315
- Publication Date: 20240315
- Accession Number: PMC10578134
- Accession Number: 10.1016/j.immuni.2023.01.032
- Accession Number: 36822205
- Source:
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