As one of the most abundant cells in the joints in rheumatoid arthritis (RA), neutrophils have long been associated with the pathogenesis of this disease, but until now, whether they had a direct role in cartilage damage was not known. The results of a new study suggest that neutrophil elastase, an enzyme present in neutrophil extracellular traps (NETs), can both degrade cartilage and stimulate downstream inflammatory processes mediated by fibroblast-like synoviocytes (FLS).

“Our group and others have shown that neutrophils may play an important role in RA initiation and perpetuation,” states co-corresponding author Carmelo Carmona-Rivera. “Neutrophils from patients with RA display an enhanced capacity to form NETs, and these lattices externalize citrullinated autoantigens and promote immune dysregulation in the synovium.”

Credit: Springer Nature Limited

“We had previously also found that FLS respond to NETs by exhibiting a pro-inflammatory phenotype, suggesting a connection between neutrophils, FLS and cartilage integrity,” adds co-corresponding author Mariana Kaplan.

In their new study, the authors showed that supernatants from NET-treated FLS from patients with RA could degrade aggrecan, one of the main components of cartilage. This degradation was not caused by aggrecanases produced by FLS or present in the NETs, but instead by NET-associated neutrophil elastase. Interestingly, this NET-derived neutrophil elastase also caused the release of peptidylarginine deiminase 2 (PAD2) from FLS.

“The release of PAD2 enhanced citrullination of the formed cartilage fragments that were in turn taken up by FLS and presented to antigen-specific CD4+ T cells, promoting their activation and the production of autoantibodies against citrullinated cartilage fragments,” explains Carmona-Rivera. “In turn, these autoantibodies activated macrophages to release pro-inflammatory cytokines that activated synovial neutrophils to release more neutrophil elastase, in a feed-forward loop that exacerbated articular inflammation.”

neutrophil elastase … can both degrade cartilage and stimulate downstream inflammatory processes

The authors suggest that this new mechanism of cartilage destruction and inflammation could be targeted therapeutically in the future. “Pathways that inhibit NET formation or the effects of molecules present in NETs could be a useful therapeutic approach for RA and its associated organ damage,” says Kaplan.