PGE₂/EP4 signaling in peripheral immune cells promotes development of experimental autoimmune encephalomyelitis

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• 作者：Susanne Schiffmann ; Andreas Weigert ; Julia M盲nnich ; Max Eberle ; Kerstin Birod ; Annett H盲ussler ; Nerea Ferreiros ; Yannick Schreiber ; Hana Kunkel ; Manuel Grez ; Benjamin Weich ; Bernhard Br眉ne ; Waltraud Pfeilschifter ; Rolf N眉sing ; Ellen Niederberger ; Sabine Gr枚sch ; Klaus Scholich ; Gerd Geisslinger
• 关键词：BMT ; bone marrow transplantation ; CFA ; complete Freund's adjuvant ; COX ; cyclooxygenase ; cPLA2 ; cytosolic phospholipase 2 ; EAE ; experimental autoimmune encephalomyelitis ; EP ; PGE2 receptor ; FACS ; fluorescence-activated cell sorting ; FCS ; fetal calf serum ; IL ; interleukin ; LC&ndash ; MS/MS ; liquid chromatography tandem mass spectrometry ; MMP9 ; matrix metalloproteinase 9 ; MOG ; myelin oligodendrocyte protein ; MRM ; multiple reaction monitoring ; MS ; multiple sclerosis ; PGE2 ; prostaglandin E2 ; PPIA ; pept
• 刊名：Biochemical Pharmacology
• 出版年：15 February, 2014
• 年：2014
• 卷：87
• 期：4
• 页码：625-635
• 全文大小：1212 K

文摘

Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated inflammatory autoimmune disease model of multiple sclerosis (MS). The inflammatory process is initiated by activation and proliferation of T cells and monocytes and by their subsequent migration into the central nervous system (CNS), where they induce demyelination and neurodegeneration. Prostaglandin E2 (PGE₂) - synthesized by cyclooxygenase 2 (COX-2) - has both pro- and anti-inflammatory potential, which is translated via four different EP receptors. We hypothesized that PGE₂ synthesized in the preclinical phase by peripheral immune cells exerts pro-inflammatory properties in the EAE model. To investigate this, we used a bone marrow transplantation model, which enables PGE₂ synthesis or EP receptor expression to be blocked specifically in peripheral murine immune cells. Our results reveal that deletion of COX-2 or its EP4 receptor in bone marrow-derived cells leads to a significant delay in the onset of EAE. This effect is due to an impaired preclinical inflammatory process indicated by a reduced level of the T cell activating interleukin-6 (IL-6), reduced numbers of T cells and of the T cell secreted interleukin-17 (IL-17) in the blood of mice lacking COX-2 or EP4 in peripheral immune cells. Moreover, mice lacking COX-2 or EP4 in bone marrow-derived cells show a reduced expression of matrix metalloproteinase 9 (MMP9), which results in decreased infiltration of monocytes and T cells into the CNS. In conclusion, our data demonstrate that PGE₂ synthesized by monocytes in the early preclinical phase promotes the development of EAE in an EP4 receptor dependent manner.