A novel mechanism for protecting the arthritic joint: microparticles deliver Annexin A1 into cartilage (146.8)

• DOI: 10.1096/fasebj.28.1_supplement.146.8
• Publication Date: 2021-06-16T09:58:03Z
• Authors: Sarah Headland; Lucy Norling; Hetal Patel; Jesmond Dalli; Stephen Kelly; Costantino Pitzalis; Francesco Dell'Accio; Mauro Perretti
• Keywords: 03 medical and health sciences; 0302 clinical medicine; 16. Peace & justice; 3. Good health

Microparticles (MPs), subcellular vesicles released from most eukaryotic cells, play important roles in inflammation. We found abundant endogenous neutrophil MPs present in rheumatoid arthritis (RA) synovial fluid compared to paired plasma analyses. These neutrophil MPs were highly enriched in Annexin A1 (AnxA1), a potent anti‐inflammatory protein. Addition of in vitro generated AnxA1+ve neutrophil MPs to IL‐1‐stimulated 3D chondrocyte cultures, rodent cartilage explants, or injected intra‐articularly in a model of inflammatory arthritis, surprisingly, afforded protection from arthritogenesis. This was evidenced by reduced matrix degradation and inflammatory mediator production and an increase in matrix‐synthesis gene expression, effects mediated primarily by AnxA1 and its receptor FPR2/ALX. Current dogma dictates that cartilage is an impenetrable avascular matrix through which metabolites must diffuse; we present the first evidence that MPs can access chondrocytes through the cartilage in vivo. Adoptive transfer of fluorescently labeled mouse neutrophils i.v. into mice at the peak of arthritis demonstrated abundant presence of MPs within arthritic cartilage (wrists, digits), but not intact (femoral head) cartilage, or in naïve mice. With this data we propose that MPs enriched with AnxA1 could offer therapeutic possibilities in the protection of cartilage in situ in arthritis patients.Grant Funding Source: Supported by The Oliver Bird Rheumatism Programme, The Nuffield Foundation; The Wellcome Trust