The role of neutrophil microparticles in rheumatoid arthritis

Microparticles are small subcellular vesicles, which function in inter-cellular communication by transferring RNA, bioactive lipids, proteins and receptors to target cells. Neutrophil microparticles are abundant in rheumatoid arthritis synovial fluids. Current dogma dictates that cartilage is an impenetrable avascular matrix through which metabolites from the synovial fluid must diffuse; we present the first evidence that microparticles can access chondrocytes through the cartilage. Addition of neutrophil microparticles to chondrocytes in vitro and in vivo afforded protection from arthritogenesis, evidenced by reduced extracellular matrix degradation, increased expression of genes involved in cartilage matrix synthesis and reduced inflammatory mediator production. Adoptive transfer of fluorescently labelled neutrophils into mice with inflammatory arthritis migrated to the inflamed joints and released microparticles, which could be found abundantly within the cartilage. We propose a mechanism whereby microparticles deliver the pro-resolving protein Annexin A1, which engages the receptor FPR2/ALX on the chondrocyte, eliciting tissue protection. This protection could be blocked in part by TGF-β neutralising antibodies and by preventing microparticle phosphatidylserine interaction with chondrocytes by coating with Annexin V. Intriguingly, microparticle treatment directly inhibited the phosphorylation of Hsp27. Hsp27 exists as large oligomers within the resting cell, and upon phosphorylation are released as monomers which function to stabilise the mRNA of certain proinflammatory genes such as IL-8, IL-6 and COX-2; which were effects seen during microparticle/chondrocyte coculture. Thus, microparticles may directly reprogram chondrocytes to prevent the expression of pro-inflammatory cytokines and mediators, but also they exert anti-inflammatory effects via the exposure of phosphatidylserine and induce the production of protective TGF-β by chondrocytes. As cartilage has limited capacity for self-repair, there is an unmet need for therapies that actively repair or protect cartilage, especially in Rheumatoid Arthritis. We envisage these microparticles could offer therapeutic possibilities in the protection of cartilage in situ in these difficult-to-treat patients.This work was supported by the Oliver Bird Rheumatism Programme, The Nuffield Foundation