Pulmonary arterial hypertension (PAH) is a serious disease characterized by arteriopathy in the small to medium-sized distal pulmonary arteries, that is associated with arterial muscularization, concentric intimal thickening, and the formation of plexiform lesions. Inflammation and autoimmunity are currently thought of as critical factors to the pathogenesis of PAH. Interleukin-6 (IL-6), a multifunctional pro-inflammatory cytokine, is elevated in the serum of pulmonary arterial hypertension (PAH) patients and can predict the survival of idiopathic (I)PAH patients. Previous animal experiments and clinical human studies indicate that IL-6 is important in the pathogenesis of PAH. We recently found that IL-6/IL-21 signaling axis plays a critical role in the pathogenesis of PAH (PNAS. 112(20): E2677, 2015). First, we found that IL-6 blockade by the monoclonal anti-IL-6 receptor antibody, MR16-1, ameliorated hypoxia-induced pulmonary hypertension (HPH) and prevented the hypoxia-induced accumulation of Th17 cells and M2 macrophages in the lungs. Furthermore, the hypoxia-induced upregulation of IL-17 and IL-21, which are primarily produced by Th17 cells, was also ameliorated by IL-6 blockade in mice. Whereas IL-17 blockade with an anti-IL-17 neutralizing antibody had no effect on HPH, IL-21 receptor-deficient mice were resistant to HPH and exhibited no significant accumulation of M2 macrophages in the lungs. Consistently, IL-21 indeed promoted the polarization of primary alveolar macrophages toward the M2 phenotype. Moreover, significantly enhanced expressions of IL-21 and M2 macrophage markers were detected in the lungs of IPAH patients who underwent lung transplantation. We are currently examining the effect of IL-21-blockade on the pathogenesis of severe PAH rat model (namely Sugen5416(Su)/hypoxia (Hx) PAH model). IL-21 receptor deletion significantly ameliorated the pathologies of Su/Hx PAH in rats. Taken together, these findings indicate that IL-21blockade might be a promising therapeutic option for refractory PAH. We would like to validate the therapeutic effect of IL-21 blockade for refractory patients with PAH in the near future.