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Myeloid-specific deletion of activating transcription factor 6 alpha increases CD11b+ macrophage subpopulations and aggravates lung fibrosis.
Mekhael, Olivia; Revill, Spencer D; Hayat, Aaron I; Cass, Steven P; MacDonald, Kyle; Vierhout, Megan; Ayoub, Anmar; Reihani, Amir; Padwal, Manreet; Imani, Jewel; Ayaub, Ehab; Yousof, Tamana; Dvorkin-Gheva, Anna; Rullo, Anthony; Hirota, Jeremy A; Richards, Carl D; Bridgewater, Darren; Stämpfli, Martin R; Hambly, Nathan; Naqvi, Asghar; Kolb, Martin Rj; Ask, Kjetil.
Afiliación
  • Mekhael O; Medical Sciences Graduate Program, McMaster University, Hamilton, Ontario, Canada.
  • Revill SD; Medical Sciences Graduate Program, McMaster University, Hamilton, Ontario, Canada.
  • Hayat AI; Department of Medicine, Firestone Institute for Respiratory Health, McMaster University and The Research Institute of St Joe's Hamilton, Hamilton, Ontario, Canada.
  • Cass SP; Medical Sciences Graduate Program, McMaster University, Hamilton, Ontario, Canada.
  • MacDonald K; Medical Sciences Graduate Program, McMaster University, Hamilton, Ontario, Canada.
  • Vierhout M; Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
  • Ayoub A; Medical Sciences Graduate Program, McMaster University, Hamilton, Ontario, Canada.
  • Reihani A; Department of Medicine, Firestone Institute for Respiratory Health, McMaster University and The Research Institute of St Joe's Hamilton, Hamilton, Ontario, Canada.
  • Padwal M; Department of Medicine, Firestone Institute for Respiratory Health, McMaster University and The Research Institute of St Joe's Hamilton, Hamilton, Ontario, Canada.
  • Imani J; Medical Sciences Graduate Program, McMaster University, Hamilton, Ontario, Canada.
  • Ayaub E; Medical Sciences Graduate Program, McMaster University, Hamilton, Ontario, Canada.
  • Yousof T; Medical Sciences Graduate Program, McMaster University, Hamilton, Ontario, Canada.
  • Dvorkin-Gheva A; Medical Sciences Graduate Program, McMaster University, Hamilton, Ontario, Canada.
  • Rullo A; Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
  • Hirota JA; Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
  • Richards CD; Department of Medicine, Firestone Institute for Respiratory Health, McMaster University and The Research Institute of St Joe's Hamilton, Hamilton, Ontario, Canada.
  • Bridgewater D; Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
  • Stämpfli MR; Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
  • Hambly N; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
  • Naqvi A; Department of Medicine, Firestone Institute for Respiratory Health, McMaster University and The Research Institute of St Joe's Hamilton, Hamilton, Ontario, Canada.
  • Kolb MR; Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
  • Ask K; Department of Medicine, Firestone Institute for Respiratory Health, McMaster University and The Research Institute of St Joe's Hamilton, Hamilton, Ontario, Canada.
Immunol Cell Biol ; 101(5): 412-427, 2023 05.
Article en En | MEDLINE | ID: mdl-36862017
ABSTRACT
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung disease of unknown etiology. The accumulation of macrophages is associated with disease pathogenesis. The unfolded protein response (UPR) has been linked to macrophage activation in pulmonary fibrosis. To date, the impact of activating transcription factor 6 alpha (ATF6α), one of the UPR mediators, on the composition and function of pulmonary macrophage subpopulations during lung injury and fibrogenesis is not fully understood. We began by examining the expression of Atf6α in IPF patients' lung single-cell RNA sequencing dataset, archived surgical lung specimens, and CD14+ circulating monocytes. To assess the impact of ATF6α on pulmonary macrophage composition and pro-fibrotic function during tissue remodeling, we conducted an in vivo myeloid-specific deletion of Atf6α. Flow cytometric assessments of pulmonary macrophages were carried out in C57BL/6 and myeloid specific ATF6α-deficient mice in the context of bleomycin-induced lung injury. Our results demonstrated that Atf6α mRNA was expressed in pro-fibrotic macrophages found in the lung of a patient with IPF and in CD14+ circulating monocytes obtained from blood of a patient with IPF. After bleomycin administration, the myeloid-specific deletion of Atf6α altered the pulmonary macrophage composition, expanding CD11b+ subpopulations with dual polarized CD38+ CD206+ expressing macrophages. Compositional changes were associated with an aggravation of fibrogenesis including increased myofibroblast and collagen deposition. A further mechanistic ex vivo investigation revealed that ATF6α was required for CHOP induction and the death of bone marrow-derived macrophages. Overall, our findings suggest a detrimental role for the ATF6α-deficient CD11b+ macrophages which had altered function during lung injury and fibrosis.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Fibrosis Pulmonar Idiopática / Lesión Pulmonar Límite: Animals Idioma: En Revista: Immunol Cell Biol Asunto de la revista: ALERGIA E IMUNOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Canadá

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Fibrosis Pulmonar Idiopática / Lesión Pulmonar Límite: Animals Idioma: En Revista: Immunol Cell Biol Asunto de la revista: ALERGIA E IMUNOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Canadá