DNGR1-Cre-mediated Deletion of Tnfaip3/A20 in Conventional Dendritic Cells Induces Pulmonary Hypertension in Mice

被引:17
作者
Koudstaal, Thomas [1 ]
van Hulst, Jennifer A. C. [1 ]
Das, Tridib [1 ]
Neys, Stefan F. H. [1 ]
Merkus, Daphne [2 ]
Bergen, Ingrid M. [1 ]
de Raaf, Michiel A. [3 ,4 ]
Bogaard, Harm Jan [4 ]
Boon, Louis [5 ]
van Loo, Geert [6 ,7 ]
Aerts, Joachim G. J., V [1 ]
Boomars, Karin A. [1 ]
Kool, Mirjam [1 ]
Hendriks, Rudi W. [1 ]
机构
[1] Erasmus MC, Dept Pulm Med, Rotterdam, Netherlands
[2] Erasmus MC, Dept Cardiol, Rotterdam, Netherlands
[3] Erasmus MC, Dept Neonatol, Rotterdam, Netherlands
[4] Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands
[5] Polpharma Biol, Utrecht, Netherlands
[6] VIB Ctr Inflammat Res, Ghent, Belgium
[7] Univ Ghent, Dept Biomed Mol Biol, Ghent, Belgium
关键词
pulmonary hypertension; dendritic cells; inflammation and immunity; pulmonary vascular remodeling; EXPRESSION; A20; IMMUNE; ANTIBODIES; LUNG; INFLAMMATION; DEFICIENCY; ACTIVATION;
D O I
10.1165/rcmb.2019-0443OC
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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-kappa B, 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. Tnfaip(3DNGRI-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-1 beta, IL-6, and IL-10 were enhanced in the lungs of Tnfaip(3DNGR1-KO) mice. Autoreactive IgA and IgG1 was detected in BAL and autoreactive IgA recognizing pulmonary endothelial antigens was present in the serum of Tnjaip3(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-kappa B pathway in DCs, through deletion of A20/Tnfaip3, leads to experimental PH with accompanied pulmonary inflammation in an IL-6-dependent fashion.
引用
收藏
页码:665 / 680
页数:16
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