| First Author | Koudstaal T | Year | 2020 |
| Journal | Am J Respir Cell Mol Biol | Volume | 63 |
| Issue | 5 | Pages | 665-680 |
| PubMed ID | 32755457 | Mgi Jnum | J:317206 |
| Mgi Id | MGI:6849523 | Doi | 10.1165/rcmb.2019-0443OC |
| Citation | Koudstaal T, et al. (2020) DNGR1-Cre-mediated Deletion of Tnfaip3/A20 in Conventional Dendritic Cells Induces Pulmonary Hypertension in Mice. Am J Respir Cell Mol Biol 63(5):665-680 |
| abstractText | 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-kappaB, 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-1beta, 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-kappaB pathway in DCs, through deletion of A20/Tnfaip3, leads to experimental PH with accompanied pulmonary inflammation in an IL-6-dependent fashion. |
