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    • Phospholipases cleave membrane phospholipids from inflammato

    2024-02-01

    Phospholipases cleave membrane phospholipids from inflammatory cells, activated platelets, erythrocytes, adipocytes and cancer PFTα (Aoki et al., 2008, Neidlinger et al., 2006). Several reports have analysed the role of LPA and its receptors in the pathogenesis of RA. Zhao et al. reported that LPA1, LPA2 and LPA3 mRNAs were detected in RA FLS, whereas LPA4 and LPA5 were not expressed. LPA1 was the main expressed receptor, followed by LPA3, and LPA2 showed the lowest expression. Nochi et al. confirmed these findings, and two recent reports demonstrated that LPA1 expression in RA FLS was significantly higher than the expression in FLS from patients with osteoarthritis (Miyabe et al., 2013, Orosa et al., 2012). More recently, Miyabe et al. (2014) have demonstrated the expression of LPA4-6 receptors in RA FLS. In addition to these expression analyses, the functional role of LPA signalling in inflammatory responses of RA FLS has been extensively studied. It has been demonstrated that LPA binds to receptors on RA FLS and through Gi/o and G12/13 proteins, induces the activation of MAPK/ERK and Rho signalling pathways. These pathways, in turn, lead to activation of NFkB transcription factor, which regulates the production of cytokines and chemokines (Fig. 1). By using antagonists of LPA1/3 receptors Zhao et al. demonstrated the role of LPA in the secretion of IL-6 and IL-8 and the synergy between LPA and TNF-α in the production of theses cytokines (Zhao et al., 2008). The main receptor involved was LPA3 and the signalling pathways were p38, pERK MAPK and Rho kinase (Zhao et al., 2008). The role of LPA in the production of COX-2 in RA FLS and the synergistic effect of LPA and IL-1β on COX-2 induction was described by Nochi et al. This effect was inhibited by treatment with Ki16425, which is a specific LPA1/3 receptor antagonist. (Nochi et al., 2008). More recently, Miyabe et al. have reported the suppression of LPA-induced proliferation of RA FLS using a new selective LPA1 receptor antagonist, LA-01. This antagonist also reduced the LPA-induced production of IL-6, CCL-2, VEGF, MMP-3 and the expression of adhesion molecules, VCAM and ICAM in these cells (Miyabe et al., 2014). Other effects of LPA that have also been demonstrated include stimulation of the migration of RA FLS (Zhao et al., 2008; Miyabe et al., 2014) and of human mesenchymal stem cells (hBMSCs) (Song et al., 2010). In a first study, Zhao et al. reported that LPA induced the migration of FLS from RA patients in an in vitro wound-closing assay. This effect was mediated by the LPA1 receptor and was regulated by p38 MAPK and Rho kinase (Zhao et al., 2008). In the same way, Miyabe et al. reported that LA-01 antagonist suppressed the LPA-induced migration of RA FLS. Completing this panorama, Song et al. (2010) showed that synovial fluid from RA patients was able to induce the migration of hBMSCs through a Boyden chamber and LPA from synovial fluid activated the LPA1 receptor to cause this effect. Interestingly, Miyabe et al. reported that LPA promote pseudoemperipolesis (which is the in vitro migration of cells beneath other cells of different lineage) of CD4+, CD8+ T and CD19+ B cells beneath RA FLS and this effect was suppressed after treatment with LA-01 (Miyabe et al., 2014).
    LPA signalling pathway in synovial apoptosis In rheumatoid arthritis, the imbalance between cell proliferation and apoptosis is pivotal for the accumulation of FLS, which contributes to synovial hyperplasia. RA FLS are resistant to apoptosis despite the expression of functional death receptors, such as Fas/CD95, TRAIL-R1, TRAIL-R2 and TNFR. In RA, FLS are strongly influenced by a plethora of cytokines, including TNF. TNF is able to induce proliferation and apoptosis in addition to its effect as an inflammatory mediator. However, in RA FLS, TNF induces proliferation and inhibits apoptosis (Aggarwal, 2003; Smeets et al., 2003; Orosa et al., 2014). The effect of LPA1 loss on TNF-induced proliferation and apoptosis of RA FLS has been assessed to determine whether LPA has a role during synovial hyperplasia (Orosa et al., 2012). The authors found that suppression of the LPA1 receptor in RA FLS abrogated the proliferation induced by TNF and sensitised the cells to TNF-induced apoptosis. This effect was associated with the upregulation of the apoptotic genes TRADD, TRAIL and PYCARD (Orosa et al., 2012). Interestingly, lpa receptor suppression did not reduce the inflammatory response of RA FLS to TNF, but rather increased the production of IL-6, IL-8 and MCP-1. This higher inflammatory response was accompanied by an increase of p38, pERK and pJNK activation (Orosa et al., 2012). Collectively, these results suggest interplay between TNF and LPA1 signalling pathways (Fig. 1) and indicate that LPA1 is a therapeutic target to block synovial hyperplasia.