Chronic perivascular inflammation is a prominent feature in the lungs of idiopathic pulmonary arterial hypertension. Although the proportions of conventional dendritic cells (cDCs) and plasmacytoid DCs are increased in idiopathic pulmonary arterial hypertension lungs, it remains unknown whether activated cDCs play a pathogenic role. The Tnfaip3 gene encodes the ubiquitin-binding protein A20, which is a negative regulator of NF-κB, critically involved in DC activation. Targeting of Tnfaip3/A20 in cDCs was achieved by Clec9a (DNGR1)-Cre–mediated excision of the Tnfaip3 gene in Tnfaip3^DNGR1-KO mice. Mice were evaluated for signs of pulmonary hypertension (PH) using right heart catheterization, echocardiography, and measurement of the Fulton index. Inflammation was assessed by immunohistochemistry and flow cytometry. Pulmonary cDCs and monocyte-derived DCs from 31-week-old Tnfaip3^DNGR1-KO mice showed modulated expression of cell surface activation markers compared with Tnfaip3^DNGR1-WT mice. Tnfaip3^DNGR1-KO mice developed elevated right ventricular systolic pressure and right ventricular hypertrophy. The lungs of these mice displayed increased vascular remodeling and perivascular and peribronchial immune cell infiltration resembling tertiary lymphoid organs. Proportions of activated T cells and expression of IL-1β, IL-6, and IL-10 were enhanced in the lungs of Tnfaip3^DNGR1-KO mice. Autoreactive IgA and IgG1 was detected in BAL and autoreactive IgA recognizing pulmonary endothelial antigens was present in the serum of Tnfaip3^DNGR1-KO mice. All signs of PH were ameliorated in Tnfaip3^DNGR1-KO mice by anti–IL-6 antibody treatment. These results indicate that activation of the NF-κB pathway in DCs, through deletion of A20/Tnfaip3, leads to experimental PH with accompanied pulmonary inflammation in an IL-6–dependent fashion.

慢性血管周围炎症是特发性肺动脉高压的肺部的突出特征。尽管在特发性肺动脉高压肺中常规树突状细胞（cDC）和浆细胞样DC的比例有所增加，但仍不清楚激活的cDC是否发挥致病作用。的TNFAIP3基因编码泛素-结合蛋白A20，这是NF-κB的负调节物，危重参与DC活化。通过Clec9a（DNGR1）-Cre介导的Tnfaip3 ^DNGR1-KO中Tnfaip3基因的切除，实现了在cDC中Tnfaip3 / A20的靶向老鼠。使用右心导管检查，超声心动图检查和Fulton指数测量评估小鼠的肺动脉高压（PH）征象。通过免疫组织化学和流式细胞术评估炎症。与Tnfaip3 ^DNGR1-WT小鼠相比，来自31周龄Tnfaip3 ^DNGR1-KO小鼠的肺cDC和单核细胞衍生的DC显示出调节的细胞表面活化标记物表达。Tnfaip3 ^DNGR1-KO小鼠出现右室收缩压升高和右室肥大。这些小鼠的肺部表现出增强的血管重塑以及类似于第三类淋巴器官的血管周围和支气管周围免疫细胞浸润。Tnfaip3 ^DNGR1-KO小鼠的肺中活化的T细胞比例和IL-1β，IL-6和IL-10的表达增强。在BAL中检测到自身反应性IgA和IgG1，Tnfaip3 ^DNGR1-KO小鼠的血清中存在识别肺动脉内皮抗原的自身反应性IgA 。PH所有的迹象都在改善TNFAIP3 ^DNGR1-KO小鼠抗-IL-6抗体治疗。这些结果表明，通过缺失A20 / Tnfaip3激活DC中的NF-κB途径会导致实验性PH并伴有以IL-6依赖性方式发生的肺部炎症。