A novel anti-inflammatory role for secretory phospholipase A2 in immune complex-mediated arthritis

Phospholipase A(2) (PLA(2)) catalyses the release of arachidonic acid for generation of lipid mediators of inflammation and is crucial in diverse inflammatory processes. The functions of the secretory PLA(2) enzymes (sPLA(2)), numbering nine members in humans, are poorly understood, though they have been shown to participate in lipid mediator generation and the associated inflammation. To further understand the roles of sPLA(2) in disease, we quantified the expression of these enzymes in the synovial fluid in rheumatoid arthritis and used gene-deleted mice to examine their contribution in a mouse model of autoimmune erosive inflammatory arthritis. Contrary to expectation, we find that the group V sPLA(2) isoform plays a novel anti-inflammatory role that opposes the pro-inflammatory activity of group IIA 5PLA(2). Mechanistically, group V sPLA(2) counter-regulation includes promotion of immune complex clearance by regulating cysteinyl leukotriene synthesis. These observations identify a novel anti-inflammatory function for a PLA(2) and identify group V 5PLA(2) as a potential biotherapeutic for treatment of immune-complex-mediated inflammation.