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

: Schiffmann, S.; Weigert, A.; Männich, J.; Eberle, M.; Birod, K.; Häussler, A.; Ferreiros, N.; Schreiber, Y.; Kunkel, H.; Grez, M.; Weichand, B.; Brüne, B.; Pfeilschifter, W.; Nüsing, R.; Niederberger, E.; Grösch, S.; Scholich, K.; Geisslinger, G.


Biochemical pharmacology 87 (2014), No.4, pp.625-635
ISSN: 0006-2952
ISSN: 1873-2968
Journal Article
Fraunhofer IME ()

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.