Neutrophils in Rheumatoid Arthritis: Breaking Immune Tolerance and Fueling Disease

Neutrophils impact the various stages of RA pathogenesis and natural history, from contributing to the loss of immune tolerance to driving synovial joint inflammation. The RA synovial microenvironment is highly conducive to the formation of NETs that externalize citrullinated proteins which have the potential to act as autoantigens and activate immune and resident cells in the synovium. Synovial neutrophils interact with fibroblast-like synoviocytes to promote proinflammatory cytokine release, MHC-dependent antigen presentation, and generation of autoantibodies. Neutrophil and NET-associated biomarkers have the potential to guide clinical treatment decisions and improve patient care. Targeting neutrophil-produced cytokines, chemokines, and NET formation are novel treatment targets that may improve outcomes for RA patients. Rheumatoid arthritis (RA), a common autoimmune disease, is characterized by a highly coordinated inflammatory response that involves innate and adaptive immunity. One of the hallmarks of RA is an immune response directed at citrullinated peptides that are specifically targeted by anticitrullinated protein antibodies (ACPAs). Among the various mechanisms by which neutrophils may promote immune dysregulation in RA, their ability to extrude neutrophil extracellular traps has recently been implicated in the development of ACPAs. In the synovium, neutrophils interact with resident fibroblast-like synoviocytes to endow them with antigen-presenting cell capabilities and an inflammatory phenotype. Further understanding how neutrophils modulate autoimmunity and tissue damage in RA may lead to the development of novel effective therapies. Rheumatoid arthritis (RA), a common autoimmune disease, is characterized by a highly coordinated inflammatory response that involves innate and adaptive immunity. One of the hallmarks of RA is an immune response directed at citrullinated peptides that are specifically targeted by anticitrullinated protein antibodies (ACPAs). Among the various mechanisms by which neutrophils may promote immune dysregulation in RA, their ability to extrude neutrophil extracellular traps has recently been implicated in the development of ACPAs. In the synovium, neutrophils interact with resident fibroblast-like synoviocytes to endow them with antigen-presenting cell capabilities and an inflammatory phenotype. Further understanding how neutrophils modulate autoimmunity and tissue damage in RA may lead to the development of novel effective therapies. an irreversible protein post-translational modification mediated by peptidyl arginine deaminases where an arginine residue is converted to citrulline. a specialized mesenchymal cell that is located within the synovium. These cells are responsible for collagen homeostasis in the articular joint, and play an important role in the pathogenesis of RA. intrinsic subcellular particles that play a variety of roles in innate defense including extracellular/intracellular pathogen killing. a subset of neutrophils found in malignancy, autoimmunity, and infection that are distinguished by their reduced buoyancy relative to normal dense granulocytes. an innate mechanism of neutrophil defense where there is extrusion of DNA strands bound to cytotoxic granule and nuclear proteins to immobilize and potentially kill invading pathogens. a family of enzymes that mediate the irreversible post-translational modification of arginine, converting it to citrulline. the first stage of rheumatoid arthritis where at-risk patients develop autoantibodies to a variety of antigens. This stage is defined by the absence of clinical arthritis, and may be incidentally discovered in clinical practice. Currently there are no recommended treatments for pre-RA. a family of chemically reactive oxygen with pathogen killing capacity and a primary role in cell signaling. a family of genetic risk alleles that predisposes individuals to develop RA, and more specifically ACPA-positive RA.