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Distinct fibroblast subsets drive inflammation and damage in arthritis.
Croft, Adam P; Campos, Joana; Jansen, Kathrin; Turner, Jason D; Marshall, Jennifer; Attar, Moustafa; Savary, Loriane; Wehmeyer, Corinna; Naylor, Amy J; Kemble, Samuel; Begum, Jenefa; Dürholz, Kerstin; Perlman, Harris; Barone, Francesca; McGettrick, Helen M; Fearon, Douglas T; Wei, Kevin; Raychaudhuri, Soumya; Korsunsky, Ilya; Brenner, Michael B; Coles, Mark; Sansom, Stephen N; Filer, Andrew; Buckley, Christopher D.
Afiliação
  • Croft AP; Rheumatology Research Group, Institute for Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK.
  • Campos J; Versus Arthritis Centre of Excellence in the Pathogenesis of Rheumatoid Arthritis, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK.
  • Jansen K; Rheumatology Research Group, Institute for Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK.
  • Turner JD; The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
  • Marshall J; Rheumatology Research Group, Institute for Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK.
  • Attar M; Rheumatology Research Group, Institute for Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK.
  • Savary L; The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
  • Wehmeyer C; Rheumatology Research Group, Institute for Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK.
  • Naylor AJ; Rheumatology Research Group, Institute for Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK.
  • Kemble S; Musculoskeletal Medicine, University of Muenster, Muenster, Germany.
  • Begum J; Rheumatology Research Group, Institute for Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK.
  • Dürholz K; Rheumatology Research Group, Institute for Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK.
  • Perlman H; Rheumatology Research Group, Institute for Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK.
  • Barone F; Rheumatology Research Group, Institute for Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK.
  • McGettrick HM; Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany.
  • Fearon DT; Department of Medicine, Division of Rheumatology, Northwestern University, Feinberg School of Medicine Chicago, Evanston, IL, USA.
  • Wei K; Rheumatology Research Group, Institute for Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK.
  • Raychaudhuri S; Rheumatology Research Group, Institute for Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK.
  • Korsunsky I; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
  • Brenner MB; Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Coles M; Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Sansom SN; Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Filer A; Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Buckley CD; The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
Nature ; 570(7760): 246-251, 2019 06.
Article em En | MEDLINE | ID: mdl-31142839
The identification of lymphocyte subsets with non-overlapping effector functions has been pivotal to the development of targeted therapies in immune-mediated inflammatory diseases (IMIDs)1,2. However, it remains unclear whether fibroblast subclasses with non-overlapping functions also exist and are responsible for the wide variety of tissue-driven processes observed in IMIDs, such as inflammation and damage3-5. Here we identify and describe the biology of distinct subsets of fibroblasts responsible for mediating either inflammation or tissue damage in arthritis. We show that deletion of fibroblast activation protein-α (FAPα)+ fibroblasts suppressed both inflammation and bone erosions in mouse models of resolving and persistent arthritis. Single-cell transcriptional analysis identified two distinct fibroblast subsets within the FAPα+ population: FAPα+THY1+ immune effector fibroblasts located in the synovial sub-lining, and FAPα+THY1- destructive fibroblasts restricted to the synovial lining layer. When adoptively transferred into the joint, FAPα+THY1- fibroblasts selectively mediate bone and cartilage damage with little effect on inflammation, whereas transfer of FAPα+ THY1+ fibroblasts resulted in a more severe and persistent inflammatory arthritis, with minimal effect on bone and cartilage. Our findings describing anatomically discrete, functionally distinct fibroblast subsets with non-overlapping functions have important implications for cell-based therapies aimed at modulating inflammation and tissue damage.
Assuntos

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Artrite Reumatoide / Fibroblastos Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans / Male Idioma: En Revista: Nature Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Artrite Reumatoide / Fibroblastos Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans / Male Idioma: En Revista: Nature Ano de publicação: 2019 Tipo de documento: Article