title: Neutrophil-derived microvesicles enter cartilage and protect the joint in inflammatory arthritis.
abstract: Microvesicles (MVs) are emerging as a new mechanism of intercellular communication by transferring cellular lipid and protein components to target cells, yet their function in disease is only now being explored. We found that neutrophil-derived MVs were increased in concentration in synovial fluid from rheumatoid arthritis patients compared to paired plasma. Synovial MVs overexpressed the proresolving, anti-inflammatory protein annexin A1 (AnxA1). Mice deficient in TMEM16F, a lipid scramblase required for microvesiculation, exhibited exacerbated cartilage damage when subjected to inflammatory arthritis. To determine the function of MVs in inflammatory arthritis, toward the possibility of MV-based therapeutics, we examined the role of immune cell-derived MVs in rodent models and in human primary chondrocytes. In vitro, exogenous neutrophil-derived AnxA1(+) MVs activated anabolic gene expression in chondrocytes, leading to extracellular matrix accumulation and cartilage protection through the reduction in stress-adaptive homeostatic mediators interleukin-8 and prostaglandin E2. In vivo, intra-articular injection of AnxA1(+) MV lessened cartilage degradation caused by inflammatory arthritis. Arthritic mice receiving adoptive transfer of whole neutrophils displayed abundant MVs within cartilage matrix and revealed that MVs, but not neutrophils themselves, can penetrate cartilage. Mechanistic studies support a model whereby MV-associated AnxA1 interacts with its receptor FPR2 (formyl peptide receptor 2)/ALX, increasing transforming growth factor-β production by chondrocytes, ultimately leading to cartilage protection. We envisage that MVs, either directly or loaded with therapeutics, can be harnessed as a unique therapeutic strategy for protection in diseases associated with cartilage degeneration.
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Headland
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Hefin R
authors.initials: HR
authors.lastname: Jones
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Lucy V
authors.initials: LV
authors.lastname: Norling
authors.affiliation: Department of Physiology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kim
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Patricia R
authors.initials: PR
authors.lastname: Souza
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Elisa
authors.initials: E
authors.lastname: Corsiero
authors.affiliation: Department of Biology, Instituto de Biociências, Letras e Ciências Exatas, São Paulo State University (UNESP), São José do Rio Preto 15054-000, Brazil.
authors.forename: Cristiane D
authors.initials: CD
authors.lastname: Gil
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Nerviani
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Department of Rheumatology, Barts Health Trust, Bancroft Road, London E1 4DG, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Dell'Accio
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Department of Rheumatology, Barts Health Trust, Bancroft Road, London E1 4DG, UK.
authors.forename: Costantino
authors.initials: C
authors.lastname: Pitzalis
authors.affiliation: Department of Biology, Instituto de Biociências, Letras e Ciências Exatas, São Paulo State University (UNESP), São José do Rio Preto 15054-000, Brazil.
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Oliani
authors.affiliation: Department of Physiology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Lily Y
authors.initials: LY
authors.lastname: Jan
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. m.perretti@qmul.ac.uk.
authors.forename: Mauro
authors.initials: M
authors.lastname: Perretti
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D002358:Cartilage, Articular / Q000473:pathology*; D006801:Humans; D051379:Mice; D009504:Neutrophils / Q000378:metabolism*; D013582:Synovial Fluid / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
chemical_list: D016212:Transforming Growth Factor beta