Prostaglandin I2 Signaling Drives Th17 Differentiation and Exacerbates Experimental Autoimmune Encephalomyelitis

by Weisong Zhou, Dustin R. Dowell, Matthew M. Huckabee, Dawn C. Newcomb, Madison G. Boswell, Kasia Goleniewska, Matthew T. Lotz, Shinji Toki, Huiyong Yin, Songyi Yao, Chandramohan Natarajan, Pingsheng Wu, Subramaniam Sriram, Richard M. Breyer, Garret A. FitzGerald, R. Stokes Peebles

Background

Prostaglandin I₂ (PGI₂), a lipid mediator currently used in treatment of human disease, is a critical regulator of adaptive immune responses. Although PGI₂ signaling suppressed Th1 and Th2 immune responses, the role of PGI₂ in Th17 differentiation is not known.

Methodology/Principal Findings

In mouse CD4⁺CD62L⁺ naïve T cell culture, the PGI₂ analogs iloprost and cicaprost increased IL-17A and IL-22 protein production and Th17 differentiation in vitro. This effect was augmented by IL-23 and was dependent on PGI₂ receptor IP signaling. In mouse bone marrow-derived CD11c⁺ dendritic cells (BMDCs), PGI₂ analogs increased the ratio of IL-23/IL-12, which is correlated with increased ability of BMDCs to stimulate naïve T cells for IL-17A production. Moreover, IP knockout mice had delayed onset of a Th17-associated neurological disease, experimental autoimmune encephalomyelitis (EAE), and reduced infiltration of IL-17A-expressing mononuclear cells in the spinal cords compared to wild type mice. These results suggest that PGI₂ promotes in vivo Th17 responses.

Conclusion

The preferential stimulation of Th17 differentiation by IP signaling may have important clinical implications as PGI₂ and its analogs are commonly used to treat human pulmonary hypertension.

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Syndicated from:PLoS ONE

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