Interleukin-6/interleukin-21 signaling axis is critical in the pathogenesis of pulmonary arterial hypertension

Abstract

IL-6 is a multifunctional proinflammatory cytokine that is elevated in the serum of patients with pulmonary arterial hypertension (PAH) and can predict the survival of patients with idiopathic PAH (IPAH). Previous animal experiments and clinical human studies indicate that IL-6 is important in PAH; however, the molecular mechanisms of IL-6-mediated pathogenesis of PAH have been elusive. Here we identified IL-21 as a downstream target of IL-6 signaling in PAH. First, we found that IL-6 blockade by the monoclonal anti-IL-6 receptor antibody, MR16-1, ameliorated hypoxiainduced pulmonary hypertension (HPH) and prevented the hypoxia-induced accumulation of Th17 cells and M2 macrophages in the lungs. Consistently, the expression levels of IL-17 and IL-21 genes, one of the signature genes for Th17 cells, were significantly up-regulated after hypoxia exposure in the lungs of mice treated with control antibody but not in the lungs of mice treated with MR16-1. Although IL-17 blockade with an anti-IL-17A 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. In accordance with these findings, IL-21 promoted the polarization of primary alveolar macrophages toward the M2 phenotype. Of note, significantly enhanced expressions of IL-21 and M2 macrophage markers were detected in the lungs of IPAH patients who underwent lung transplantation. Collectively, these findings suggest that IL-21 promotes PAH in association with M2 macrophage polarization, downstream of IL-6-signaling. The IL-6/IL-21-signaling axis may be a potential target for treating PAH.pulmonary arterial hypertension | interleukin-21 | interleukin-6 | Th17 cells | M2 macrophage

Protective Roles of Endothelial AMP-Activated Protein Kinase Against Hypoxia-Induced Pulmonary Hypertension in Mice

“…In contrast, in this study, we found significantly less IL-6 levels in the eAMPK −/− lung homogenates under chronic hypoxia compared with control lung homogenates. The discrepancy between the study by Hashimoto-Kataoka et al 50 and our study could be explained, at least in part, by the difference in the experimental settings, as they used WT mice and we used endothelial-specific AMPKknockout mice and chronic hypoxia. Indeed, IL-6 is known as a hormone that has both proinflammatory and anti-inflammatory actions.…”

“…Third, several studies demonstrated that IL-6 plays a crucial role in the development of PH. Among them, Hashimoto-Kataoka et al 50 demonstrated the crucial role of IL-6 in the pathogenesis of PAH. In contrast, in this study, we found significantly less IL-6 levels in the eAMPK −/− lung homogenates under chronic hypoxia compared with control lung homogenates.…”

Potassium Channel Subfamily K Member 3 (KCNK3) Contributes to the Development of Pulmonary Arterial Hypertension

“…For instance and in accordance with our results, (1) TIMP-1 is overexpressed by cultured PASMCs from patients with iPAH, 32 and in vivo TIMP-1 gene transfer occurs in ratpotentialized PAH induced by chronic hypoxia 33 ; (2) MCP-1/ CCL2 is strongly involved in the development of human and experimental PAH 34,35 and plays a key role in arterial remodeling though direct mitotic/chemotactic effects on PASMCs and PAECs but also recruits monocytes/mononuclear cells and populations of circulating progenitors 36,37 ; and (3) there is an IL-17-dependent (Th17) immune polarization in PAH 38 and IL-17 mRNA, and protein expression is significantly increased in hypoxia-induced PH mouse models. 39 Interestingly, IL-17 binds to its receptor composed of IL-17RA and IL-17RC subtypes, leading to activation of the canonical ERK1/2, phosphoinositide 3-kinase-Akt, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase pathways. 40 We have shown that KCNK3 expression was reduced in patients with iPAH and hPAH and in MCT-PH rats.…”

Pulmonary tumour thrombotic microangiopathy

“…Therefore, crosstalk between tumour cells, macrophages and intimal cells may occur through the osteopontin-CD44 axis to drive both tumorigenesis and ongoing macrophage recruitment. Macrophage-derived factors, such as interleukin-6 (IL-6), as implicated in PAH [20], may also contribute to the fibrointimal proliferation in PTTM. Tumour cell nests are also evident in pulmonary veins and lymphatics [9,10,18], with evidence for lymphatic tumour invasion (Fig.…”