Despite common pathological features in both asthma and PAH, such as inflammation, easy muscle constriction, and SMC proliferation, allergy exposure leads to remodeling of both bronchi and pulmonary vessels in rodents (Rydell-T?rm?nen et al., 2008a,b). easy muscle cell proliferation through activation of STAT6. These results demonstrate the crucial role of CRTH2-mediated Th2 response in PAH pathogenesis and spotlight the CRTH2 receptor as a potential therapeutic target for PAH. Introduction Pulmonary arterial hypertension (PAH) is usually a pathophysiological disorder characterized by remodeling of the pulmonary arteries (PAs), resulting in a progressive increase in Toltrazuril sulfone pulmonary vascular resistance, right ventricular (RV) hypertrophy, and ultimately right Toltrazuril sulfone heart failure (Gali et al., 2016). Although significant progress has been made in the treatment of PAH in the past several decades, current pharmacological approaches such as endothelin receptor antagonists, vasodilators, and phosphodiesterase inhibitors provide mainly symptomatic relief with few improvements in overall survival (Rabinovitch, 2012). As a severe and debilitating lung disease, PAH still contributes to unacceptably high morbidity and mortality of patients with cardiopulmonary diseases (Benza et al., 2010). Therefore, identifying new molecules or signaling pathways triggering or mediating PA remodeling, which may serve as potential therapeutic targets, is urgently needed. Pulmonary arterial easy muscle cell (SMC [PASMC]) proliferation and hypertrophy and extracellular matrix deposition contribute to medial hypertrophy and muscularization, leading to narrowness or obstruction of PAs and sustained elevation of pulmonary arterial pressure (Rabinovitch, 2012). Emerging studies exhibited that perivascular immune and inflammatory responses play an essential role in the pathogenesis of idiopathic PAH (Savai et al., 2012; Stacher et al., 2012; Yeager et al., 2012). Moreover, elevated serum levels of multiple inflammatory cytokines and chemokines are also observed in patients with PAH (Anwar et al., 2016). Of note, marked infiltration of CD4+ T cells is usually observed around PAs in patients with PAH (Savai et al., 2012). In experimental PAH animal models, different soluble antigens such as and OVA Toltrazuril sulfone could induce severe muscularization in PAs and PAH by triggering CD4+ T helper 2 (Th2) response (Daley et al., 2008). In addition, Th2 cytokines, IL-4 and IL-13, are involved in the development of PAH in multiple PAH animal models (Park et al., 2014; Yamaji-Kegan et al., 2014; Kumar et al., 2015). These observations suggest that Th2-mediated immune reaction is usually implicated in the pathogenesis of PAH and may be used as an intervention option for PAH therapy. G proteinCcoupled receptor 44 (GPR44) structurally belongs to the family of chemoattractant receptors (Marchese et al., 1999). It is selectively expressed in Th2 lineage cells and, thus, is Rabbit Polyclonal to TNAP1 named chemoattractant receptor homologous molecule expressed on Th2 (CRTH2; Nagata et al., 1999b). Prostaglandin (PG) D2 is usually a natural ligand for CRTH2 receptor; its activation can induce intracellular Ca2+ mobilization and chemotaxis in Th2 cells in a Gi-dependent fashion (Hirai et al., 2001). Moreover, PGD2 preferentially elicits the secretion of proinflammatory cytokines such as IL-4, IL-5, and IL-13 in Th2 cells in a dose-dependent manner through CRTH2 (Xue et al., 2005). Additionally, immunoglobulin E-stimulated mast cells invoke IL-4 and IL-13 production by Th2 cells through interaction of PGD2 and CRTH2 on Th2 cells (Xue et al., 2009). Therefore, activation of CRTH2 increases pulmonary allergic inflammation in mice and humans (Spik et al., 2005; Schmidt et al., 2013; Palikhe et al., 2016). However, whether CRTH2-mediated Th2 cell activation contributes to the development of PAH remains unclear. In this study, we demonstrated that CRTH2 expression in circulating CD4+ T cells and serum Th2 cytokines was elevated in patients with PAH and in PAH mouse models. CRTH2 deficiency attenuated the development of hypoxia-induced PAH in mice by suppression of Th2 immune responses in the lungs. CRTH2+/+ bone marrow (BM) transplantation (BMT) or CRTH2+/+ T cell adoptive transfer augmented hypoxia + OVA (HyOA)Cinduced PAH in CRTH2?/? mice, which was ameliorated by neutralization of both IL-4 and IL-13. Inhibition of CRTH2 alleviated HyOA-induced PAH in mice. Mechanistically, Th2 cellCderived IL-4 and IL-13 promoted PASMC proliferation by activation of STAT6. These results demonstrated that CRTH2-mediated Th2 activation is implicated in the pathogenesis of PAH. Results Enhanced Th2 immune response in patients with PAH and in mice exposed to chronic hypoxia Inflammation and autoimmunity.