Abstract
Interleukin-6 (IL-6) is a multifunctional pro-inflammatory cytokine 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; however, the molecular mechanisms of IL-6-mediated pathogenesis of PAH have been elusive. We recently identified IL-21 as a novel downstream cytokine of IL-6-signaling in PAH. 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. Together, the above data suggest that IL-21 promotes PAH through M2 macrophage polarization, downstream of IL-6-signaling. IL-6/Th17/IL-21-signaling axis might be a novel potential target for treating PAH.
Highlights
Pulmonary arterial hypertension (PAH) is a serious disease characterized by arteriopathy in the small- to medium-sized distal pulmonary arteries, which is associated with arterial muscularization, concentric intimal thickening, and the formation of plexiform lesions [1, 2]
We recently reported that the IL-6/interleukin- 21(IL-21)-signaling axis played critical roles for the development of hypoxia-induced pulmonary hypertension (HPH) in association with M2 macrophage polarization [13]
We found that the Il-21 mRNA level peaked on day 2, remained elevated until day 14, and returned to the basal levels on day 28 after hypoxia exposure
Summary
Pulmonary arterial hypertension (PAH) is a serious disease characterized by arteriopathy in the small- to medium-sized distal pulmonary arteries, which is associated with arterial muscularization, concentric intimal thickening, and the formation of plexiform lesions [1, 2]. Inflammation and autoimmunity are currently thought of as critical factors to the pathogenesis of PAH [3, 4] Inflammatory cells such as T cells, B cells, and macrophages infiltrate the plexiform lesions in patients with advanced PAH. Patients with idiopathic (I)PAH exhibit increased IL-6 serum levels, which correlate with their prognoses [3, 9, 10] Consistent with these findings, lung-specific IL-6 transgenic mice display spontaneous PH in normoxia and develop greatly exaggerated hypoxia-induced PH (HPH) [11], whereas IL-6-deficient mice show resistance to HPH [12]. We recently reported that the IL-6/interleukin- 21(IL-21)-signaling axis played critical roles for the development of HPH in association with M2 macrophage polarization [13] In this manuscript, we elaborate on the role of IL-6/IL-21-signaing axis in the pathogenesis of PAH
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
