RT Journal Article
SR Electronic
T1 Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis
JF Science Immunology
JO Sci. Immunol.
FD American Association for the Advancement of Science
SP eaag3358
DO 10.1126/sciimmunol.aag3358
VO 2
IS 10
A1 Carmona-Rivera, Carmelo
A1 Carlucci, Philip M.
A1 Moore, Erica
A1 Lingampalli, Nithya
A1 Uchtenhagen, Hannes
A1 James, Eddie
A1 Liu, Yudong
A1 Bicker, Kevin L.
A1 Wahamaa, Heidi
A1 Hoffmann, Victoria
A1 Catrina, Anca Irinel
A1 Thompson, Paul R.
A1 Buckner, Jane H.
A1 Robinson, William H.
A1 Fox, David A.
A1 Kaplan, Mariana J.
YR 2017
UL http://immunology.sciencemag.org/content/2/10/eaag3358.abstract
AB Neutrophil extracellular traps (NETs) activate synovial fibroblast-like synoviocytes (FLS) in joints of individuals with rheumatoid arthritis. Now, Carmona-Rivera et al. investigate the mechanism behind this activation. They found that NETs containing citrullinated peptides could be internalized by FLS through the RAGE-TLR9 pathway and then loaded onto major histocompatibility complex class II and presented to antigen-specific T cells, which contribute to joint inflammation. NET-loaded FLS induced autoantibody production and joint disease in mice. These data suggest that cross-talk between NETs and FLS may contribute to rheumatoid arthritis.Rheumatoid arthritis (RA) is characterized by synovial joint inflammation and by development of pathogenic humoral and cellular autoimmunity to citrullinated proteins. Neutrophil extracellular traps (NETs) are a source of citrullinated autoantigens and activate RA synovial fibroblast-like synoviocytes (FLS), cells crucial in joint damage. We investigated the molecular mechanisms by which NETs promote proinflammatory phenotypes in FLS and whether these interactions generate pathogenic anti-citrulline adaptive immune responses. NETs containing citrullinated peptides are internalized by FLS through a RAGE-TLR9 pathway, promoting FLS inflammatory phenotype and their up-regulation of major histocompatibility complex (MHC) class II. Once internalized, arthritogenic NET peptides are loaded into FLS MHC class II and presented to antigen-specific T cells. HLA-DRB1*04:01 transgenic mice immunized with mouse FLS loaded with NETs develop antibodies specific to citrullinated forms of relevant autoantigens implicated in RA pathogenesis as well as cartilage damage. These results implicate FLS as notable mediators in RA pathogenesis, through the internalization and presentation of NET citrullinated peptides to the adaptive immune system, leading to pathogenic autoimmunity and cartilage damage.