Th17 polarization in pulmonary arterial hypertension

Abstract

Background Inflammation may contribute to the pathobiology of pulmonary arterial hypertension (PAH). Deciphering the PAH fingerprint on the immune response orchestrated by dendritic and T cells (DC and L T ) may allow the identification of potential immunopathological approaches to PAH management. Methods We performed an immunophenotyping of monocyte-derived DC (MoDC) and circulating lymphocytes from idiopathic PAH (iPAH) and control patients by flow-cytometry. Using the same technic, we performed cytokine profiling of both populations after stimulation and/or coculture. We tested the immunomudulatory effects of glucocorticoid (dexamethasone/Dex) on this immunophenotype and cytokine profile. We confirmed by an epigenetic approach, the immune polarization of PAH patients in blood DNA. Results PAH MoDCs displayed similar profile of membrane costimulatory molecules as compared to controls. However, PAH MoDCs retained higher level of the T cell activating molecules CD86 and CD40 after Dex pretreatment than controls. This was associated with an increased expression of IL-12p40 and a reduced migration toward CCL21. Moreover, both with and without Dex, PAH MoDC induced a higher activation and proliferation of CD4+ T cells, associated to a reduced expression of IL-4 (Th2 response) and a higher expression of IL-17 (Th17 response). Purified PAH CD4+ T cells expressed higher level of IL-17 after activation than controls. At last, there was a significant increase in the percentage of demethylated DNA at the IL-17 promoter, in the PAH blood DNA as compared to controls. Conclusions We highlighted a Th17 immune polarization in PAH patient; a polarization involved in several chronic inflammatory and autoimmune conditions.