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Central Role of Dendritic Cells in Pulmonary Arterial Hypertension in Human and Mice.

Published version
Peer-reviewed

Type

Article

Change log

Authors

van Uden, Denise 
Koudstaal, Thomas 
van Hulst, Jennifer AC 
Bergen, Ingrid M 
Gootjes, Chelsea 

Abstract

The pathogenesis of idiopathic pulmonary arterial hypertension (IPAH) is not fully understood, but evidence is accumulating that immune dysfunction plays a significant role. We previously reported that 31-week-old Tnfaip3DNGR1-KO mice develop pulmonary hypertension (PH) symptoms. These mice harbor a targeted deletion of the TNFα-induced protein-3 (Tnfaip3) gene, encoding the NF-κB regulatory protein A20, specifically in type I conventional dendritic cells (cDC1s). Here, we studied the involvement of dendritic cells (DCs) in PH in more detail. We found various immune cells, including DCs, in the hearts of Tnfaip3DNGR1-KO mice, particularly in the right ventricle (RV). Secondly, in young Tnfaip3DNGR1-KO mice, innate immune activation through airway exposure to toll-like receptor ligands essentially did not result in elevated RV pressures, although we did observe significant RV hypertrophy. Thirdly, PH symptoms in Tnfaip3DNGR1-KO mice were not enhanced by concomitant mutation of bone morphogenetic protein receptor type 2 (Bmpr2), which is the most affected gene in PAH patients. Finally, in human IPAH lung tissue we found co-localization of DCs and CD8+ T cells, representing the main cell type activated by cDC1s. Taken together, these findings support a unique role of cDC1s in PAH pathogenesis, independent of general immune activation or a mutation in the Bmpr2 gene.

Description

Keywords

BMPR2, Tnfaip3, Toll-like receptor, dendritic cells, inflammation, pulmonary arterial hypertension, Animals, Bone Morphogenetic Protein Receptors, Type II, Dendritic Cells, Familial Primary Pulmonary Hypertension, Gene Deletion, Heart Ventricles, Humans, Immunity, Innate, Mice, Mutation, Toll-Like Receptor 4, Tumor Necrosis Factor alpha-Induced Protein 3

Journal Title

Int J Mol Sci

Conference Name

Journal ISSN

1661-6596
1422-0067

Volume Title

22

Publisher

MDPI AG
Sponsorship
British Heart Foundation (None)