Prostaglandin I₂ Signaling Drives Th17 Differentiation and Exacerbates Experimental Autoimmune Encephalomyelitis

<div><h3>Background</h3><p>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.</p> <h3>Methodology/Principal Findings</h3><p>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 <em>in vitro</em>. 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 <em>in vivo</em> Th17 responses.</p> <h3>Conclusion</h3><p>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.</p>