Inhibition of lysophosphatidic acid receptor ameliorates Sjogren's syndrome in NOD mice
- Authors
- Park, Eunhye; Kim, Donghee; Lee, Song Mi; Jun, Hee-Sook
- Issue Date
- Apr-2017
- Publisher
- IMPACT JOURNALS LLC
- Keywords
- Sjogren' s syndrome; LPA; Ki16425; NOD mice; IL-17
- Citation
- ONCOTARGET, v.8, no.16, pp.27240 - 27251
- Journal Title
- ONCOTARGET
- Volume
- 8
- Number
- 16
- Start Page
- 27240
- End Page
- 27251
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/6221
- DOI
- 10.18632/oncotarget.15916
- ISSN
- 1949-2553
- Abstract
- Lysophosphatidic acid (LPA), a bioactive lysophospholipid, is involved in the pathogenesis of chronic inflammatory and autoimmune diseases. In this study, we investigated the role of LPA/LPA receptor (LPAR) signaling in the pathogenesis of Sjogren's syndrome (SS). We found that autotaxin, an LPA producing enzyme, and LPAR1 and LPAR3 mRNA, and IL-17 mRNA were highly expressed in the exocrine glands of 20-week-old nonobese diabetic (NOD) mice, which show SS symptoms at this age, as compared with non-symptomatic 8-week-old NOD mice. In an adoptive transfer model using NOD lymphocytes, treatment with Ki16425, an LPAR1/3 antagonist, restored tear and saliva secretion and decreased symptoms of SS compared with the vehicle-treated group. IL-17 levels in serum and lacrimal glands were also significantly reduced by Ki16425 in recipient mice. In addition, Ki16425 treatment of 20-week-old NOD mice, which spontaneously developed SS, restored saliva volume. Treatment of NOD splenocytes with LPA induced the expression of IL-17 in a dose-dependent manner, and Ki16425 inhibited this increase. LPA stimulated the activation of ROCK2 and p38 MAPK; and inhibition of ROCK2 or p38 MAPK suppressed LPA-induced IL-17 expression. Our data suggest that LPAR signaling stimulates SS development by induction of IL-17 production via ROCK and p38 MAPK pathways. Thus, LPAR inhibition could be a possible therapeutic strategy for SS.
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