Aryl hydrocarbon receptor is essential for the pathogenesis of pulmonary arterial hypertension [PBMC]

Pulmonary arterial hypertension (PAH) is a devastating disease characterized by arteriopathy in the small to medium-sized distal pulmonary arteries, often accompanied by infiltration of inflammatory cells. Aryl hydrocarbon receptor (AHR), a nuclear receptor/transcription factor, detoxifies xenobiotics and regulates the differentiation and function of various immune cells. However, the role of AHR in the pathogenesis of PAH is largely unknown. Here, we explore the role of AHR in the pathogenesis of PAH. AHR agonistic activity in serum was significantly higher in PAH patients than in healthy volunteer and was associated with poor prognosis of PAH. Sprague-Dawley (SD) rats treated with the potent endogenous AHR agonist, 6-formylindolo[3,2-b]carbazole in combination with hypoxia develop severe pulmonary hypertension (PH) with plexiform-like lesions, whereas SD rats treated with the potent vascular endothelial growth factor receptor 2 inhibitors did not. Ahr-knockout (Ahr-/-) rats generated using the CRISPR/Cas9 system did not develop PH in the SU5416/hypoxia model. A diet containing Qing-Dai, a Chinese herbal drug, in combination with hypoxia led to development of PH in Ahr+/+ rats, but not in Ahr-/- rats. RNA-seq analysis, ChIP-seq analysis, immunohistochemical analysis, and bone marrow transplantation experiments shows that activation of several inflammatory signaling pathways were upregulated in endothelial cells and peripheral blood mononuclear cells, which led to infiltration of CD4+ IL-21+ T cells and MRC1+ macrophages into vascular lesions in an AHR-dependent manner. Taken together, AHR plays crucial roles in the development and progression of PAH and the AHR signaling pathway represents a promising novel therapeutic target for PAH肺动脉高压（Pulmonary arterial hypertension, PAH）是一类以中小型远端肺动脉动脉病变为特征的毁灭性疾病，常伴随炎性细胞浸润。芳基烃受体（Aryl hydrocarbon receptor, AHR）作为一种核受体/转录因子，可介导外源性物质的解毒代谢，并调控多种免疫细胞的分化与功能。然而，AHR在PAH发病机制中的作用目前仍在很大程度上尚不明确。本研究旨在探究AHR在PAH发病机制中的作用。研究发现，PAH患者血清中的AHR激动活性显著高于健康志愿者，且与PAH的不良预后密切相关。使用强效内源性AHR激动剂6-甲酰基吲哚并[3,2-b]咔唑联合低氧处理的斯普拉格-道利（SD）大鼠，可发展为伴有丛状样病变的重度肺动脉高压；而仅给予强效血管内皮生长因子受体2抑制剂的SD大鼠则未出现该表型。利用CRISPR/Cas9系统构建的Ahr基因敲除（Ahr-/-）大鼠，在SU5416/低氧模型中未发生肺动脉高压。含中草药青黛的饲料联合低氧处理，可使Ahr+/+大鼠发展为肺动脉高压，但Ahr-/-大鼠无此表型。RNA测序（RNA-seq）、染色质免疫共沉淀测序（ChIP-seq）、免疫组化分析及骨髓移植实验结果显示，多条炎性信号通路在内皮细胞与外周血单个核细胞中被上调，进而以AHR依赖的方式促使CD4+IL-21+ T细胞与MRC1+巨噬细胞浸润至血管病变部位。综上，AHR在PAH的发生与进展中发挥关键作用，AHR信号通路有望成为PAH全新的极具前景的治疗靶点。