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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; Lizama, Carlos O; Matthay, Michael; Wolters, Paul; Molofsky, Ari B; Peng, Tien.
Afiliación
  • Wang C; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Zhongshan Institute for Drug Discovery, Chinese Academy of Sciences, Zhongshan 528400, China.
  • Hyams B; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Cardiovascular Institute and Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Allen NC; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Cardiovascular Institute and Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Cautivo K; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Monahan K; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Cardiovascular Institute and Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Zhou M; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Cardiovascular Institute and Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Dahlgren MW; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Lizama CO; Cardiovascular Institute and Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Matthay M; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Wolters P; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Molofsky AB; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: ari.molofsky@ucsf.edu.
  • Peng T; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Cardiovascular Institute and Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar ImmunoX Initiative, University of
Immunity ; 56(3): 576-591.e10, 2023 03 14.
Article en En | MEDLINE | ID: mdl-36822205
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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Enfisema Pulmonar / Enfermedad Pulmonar Obstructiva Crónica / Enfisema Límite: Animals / Humans Idioma: En Revista: Immunity Asunto de la revista: ALERGIA E IMUNOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: China
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Enfisema Pulmonar / Enfermedad Pulmonar Obstructiva Crónica / Enfisema Límite: Animals / Humans Idioma: En Revista: Immunity Asunto de la revista: ALERGIA E IMUNOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: China