Lysophosphatidic acid mediates the pathogenesis of psoriasis by activating keratinocytes through LPAR5

LPA, a glycerophospholipid, is significantly upregulated in psoriasis that facilitates IMQ-induced psoriasis-like inflammation in a mouse model as well as increases the expression of inflammatory mediators in KCs, however, LPA does not affect on KCs proliferation or Th1,17 cells differentiation. Interestingly, psoriasis-like inflammation can be alleviated by inhibiting the production of LPA through ATX inhibitor. Furthermore, LPAR5 is over-expressed in psoriatic lesion and genetic knock out of LPAR5 suppresses the LPA plus IMQ-induced psoriatic phenotype in mice, meanwhile, LPAR5 antagonist abrogates LPA induced expression of inflammatory mediators in KCs. ROCKs or DAG/PKD1 is a typical downstream signaling pathway of LPAR5 and we found DAG is also raised in plasma of psoriasis patients. LPA increases DAG or ROCKs expression that activates PKD1,leading to activate NF-kB and Stat1 signaling pathway. Through RNA-Seq techniques, we validated differentially expressed genes including TLR2 regulated by LPA. Knock down of Stat1 expression or LPAR5 antagonist significantly attenuates LPA induced TLR2 expression or Stat1 activation, indicating that LPA/LPAR5 plays a critical role in the pathogenesis of psoriasis.