Central role of dendritic cells in pulmonary arterial hypertension in human and mice

D Uden, Thomas Koudstaal, Jennifer van Hulst, Ingrid Bergen, C (Chelsea) Gootjes, NW Morrell, G van Loo, Jan von der Thüsen, Thierry van den Bosch, MR Ghigna, F Perros, D Montani, Mirjam Kool, Karin Boomars, Rudi Hendriks

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The pathogenesis of idiopathic pulmonary arterial hypertension (IPAH) is not fully under-stood, 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.

Original languageEnglish
Article number1756
Pages (from-to)1-19
Number of pages19
JournalInternational Journal of Molecular Sciences
Issue number4
Publication statusPublished - 10 Feb 2021

Bibliographical note

Funding Information:
Funding: This research was funded by Dutch Heart Foundation, grant number 2016T052 (D.v.U./ M.K.). T.K. was supported by an unrestricted grant by Actelion Pharmaceuticals and the Pulmonary hypertension Patients Association.

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© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

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