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

Abstract

Phospholipase A2 (PLA2) 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 PLA2 enzymes (sPLA2), 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 sPLA2 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 sPLA2 isoform plays a novel anti-inflammatory role that opposes the pro-inflammatory activity of group IIA sPLA2. Mechanistically, group V sPLA2 counter-regulation includes promotion of immune complex clearance by regulating cysteinyl leukotriene synthesis. These observations identify a novel anti-inflammatory function for a PLA2 and identify group V sPLA2 as a potential biotherapeutic for treatment of immune-complex-mediated inflammation.

Platelet microparticles are internalized in neutrophils via the concerted activity of 12-lipoxygenase and secreted phospholipase A 2 -IIA

“…Indeed, studies have identified platelet-type 12-LO in skin fibroblasts and in fibroblast-like synoviocytes from patients with psoriasis and RA (68,69), suggesting that MPs derived from these cells also might be capable of conveying 12-LO and of using 12(S)-HETE to promote their internalization. Because both platelet MPs and sPLA 2 -IIA are present in inflamed SF (21,28), one might ask whether 12(S)-HETE is found in RA SF. Of interest is that 5,12 (S)-diHETE, which is produced only through the coordinated action of leukocyte 5-lipoxygenase and platelet 12-LO, is the most abundant eicosanoid in SF of patients with RA (70), thus suggesting the potential for platelet MP internalization in neutrophils.…”

“…Although 10 different groups of sPLA 2 enzymes have been identified in humans, sPLA 2 group IIA (sPLA 2 -IIA) is (nonexclusively) expressed by platelets and is induced in inflammation (27,28). In RA, sPLA 2 -IIA is overexpressed in joint lubricating synovial fluid (SF) and amplifies the disease (28). Whereas sPLA 2 -IIA has limited activity on the cellular plasma membrane (27), it uses MPs as a substrate (27,29,30).…”

“…Whereas sPLA 2 -IIA has limited activity on the cellular plasma membrane (27), it uses MPs as a substrate (27,29,30). Like sPLA 2 -IIA, MPs accumulate in SF during RA, where they are frequently associated with neutrophils (11,21,28,31,32).…”

“…The secreted phospholipase A 2 (sPLA 2 ) enzymes hydrolyze membrane phospholipids in the sn-2 position, generating free fatty acids and lysophospholipids (27). Although 10 different groups of sPLA 2 enzymes have been identified in humans, sPLA 2 group IIA (sPLA 2 -IIA) is (nonexclusively) expressed by platelets and is induced in inflammation (27,28). In RA, sPLA 2 -IIA is overexpressed in joint lubricating synovial fluid (SF) and amplifies the disease (28).…”

“…We next used the K/BxN serum transfer model of arthritis, a disease model in which both sPLA 2 -IIA and platelet MPs are implicated (21,28), to validate the MP internalization process in inflammation. Because C57Bl6/J mice naturally lack sPLA 2 -IIA (28), we used transgenic mice expressing human sPLA 2 -IIA (sPLA 2 -IIA TGN , in a C57Bl6/J background) (44) and included WT C57Bl6/J mice as controls.…”