title: Immune-Regulatory Molecule CD69 Controls Peritoneal Fibrosis.
abstract: Patients with ESRD undergoing peritoneal dialysis develop progressive peritoneal fibrosis, which may lead to technique failure. Recent data point to Th17-mediated inflammation as a key contributor in peritoneal damage. The leukocyte antigen CD69 modulates the setting and progression of autoimmune and inflammatory diseases by controlling the balance between Th17 and regulatory T cells (Tregs). However, the relevance of CD69 in tissue fibrosis remains largely unknown. Thus, we explored the role of CD69 in fibroproliferative responses using a mouse model of peritoneal fibrosis induced by dialysis fluid exposure under either normal or uremic status. We found that cd69-/-mice compared with wild-type (WT) mice showed enhanced fibrosis, mesothelial to mesenchymal transition, IL-17 production, and Th17 cell infiltration in response to dialysis fluid treatment. Uremia contributed partially to peritoneal inflammatory and fibrotic responses. Additionally, antibody-mediated CD69 blockade in WT mice mimicked the fibrotic response of cd69-/-mice. Finally, IL-17 blockade in cd69-/-mice decreased peritoneal fibrosis to the WT levels, and mixed bone marrow from cd69-/-and Rag2-/-γc-/-mice transplanted into WT mice reproduced the severity of the response to dialysis fluid observed in cd69-/-mice, showing that CD69 exerts its regulatory function within the lymphocyte compartment. Overall, our results indicate that CD69 controls tissue fibrosis by regulating Th17-mediated inflammation.
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Georgios
authors.initials: G
authors.lastname: Liappas
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Guadalupe Tirma
authors.initials: GT
authors.lastname: González-Mateo
authors.affiliation: Signaling and Inflammation Program, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Sánchez-Díaz
authors.affiliation: Signaling and Inflammation Program, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Lazcano
authors.affiliation: Signaling and Inflammation Program, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Lasarte
authors.affiliation: Signaling and Inflammation Program, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors.forename: Adela
authors.initials: A
authors.lastname: Matesanz-Marín
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología Consejo Superior de Investigaciones Científicas, Madrid, Spain.
authors.forename: Rafal
authors.initials: R
authors.lastname: Zur
authors.affiliation: Department of Molecular Cell Biology and Immunology, Vrije Universiteit University Medical Center Vrije Universiteit Medisch Centrum, Amsterdam, The Netherlands.
authors.forename: Evelina
authors.initials: E
authors.lastname: Ferrantelli
authors.affiliation: Molecular Biology Unit and.
authors.forename: Laura García
authors.initials: LG
authors.lastname: Ramírez
authors.affiliation: Molecular Biology Unit and.
authors.forename: Abelardo
authors.initials: A
authors.lastname: Aguilera
authors.affiliation: Molecular Biology Unit and.
authors.forename: Elena
authors.initials: E
authors.lastname: Fernández-Ruiz
authors.affiliation: Department of Molecular Cell Biology and Immunology, Vrije Universiteit University Medical Center Vrije Universiteit Medisch Centrum, Amsterdam, The Netherlands.
authors.forename: Robert H J
authors.initials: RH
authors.lastname: Beelen
authors.affiliation: Nephrology Department, Hospital Universitario La Paz, Instituto de Investigación Sanitaria La Paz, Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Selgas
authors.affiliation: Signaling and Inflammation Program, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.|Immunology Department, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain; and.
authors.forename: Francisco
authors.initials: F
authors.lastname: Sánchez-Madrid
authors.affiliation: Signaling and Inflammation Program, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain; pmartinf@cnic.es mlcabrera@cbm.csic.es.
authors.forename: Pilar
authors.initials: P
authors.lastname: Martín
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas Universidad Autónoma de Madrid, Madrid, Spain; pmartinf@cnic.es mlcabrera@cbm.csic.es.
authors.forename: Manuel
authors.initials: M
authors.lastname: López-Cabrera
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology* / Q000502:physiology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology* / Q000502:physiology; D005260:Female; D037181:Lectins, C-Type / Q000172:deficiency / Q000276:immunology* / Q000502:physiology; D051379:Mice; D056627:Peritoneal Fibrosis / Q000276:immunology*; D058504:Th17 Cells / Q000502:physiology; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D037181:Lectins, C-Type; D000099192:CD69 Antigens
keywords: Chronic inflammation; Immunology and pathology; dialysis; fibrosis