Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in 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.