Dysregulated lung stroma drives emphysema exacerbation by potentiating resident lymphocytes to suppress an epithelial stem cell reservoir.

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  • 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:
      Pulmonary Emphysema*/genetics ; Emphysema* ; Pulmonary Disease, Chronic Obstructive*; Humans ; Mice ; Animals ; Lung ; Lymphocytes ; Stem Cells
    • 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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    • 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