{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T01:50:12Z","timestamp":1788313812965,"version":"build-2803163510"},"reference-count":44,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,10]],"date-time":"2021-02-10T00:00:00Z","timestamp":1612915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002996","name":"Hartstichting","doi-asserted-by":"publisher","award":["2016T052"],"award-info":[{"award-number":["2016T052"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 TNF\u03b1-induced protein-3 (Tnfaip3) gene, encoding the NF-\u03baB 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.<\/jats:p>","DOI":"10.3390\/ijms22041756","type":"journal-article","created":{"date-parts":[[2021,2,12]],"date-time":"2021-02-12T00:49:26Z","timestamp":1613090966000},"page":"1756","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Central Role of Dendritic Cells in Pulmonary Arterial Hypertension in Human and Mice"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4120-8900","authenticated-orcid":false,"given":"Denise","family":"van Uden","sequence":"first","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Koudstaal","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer A. C.","family":"van Hulst","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid M.","family":"Bergen","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chelsea","family":"Gootjes","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas W.","family":"Morrell","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cambridge &amp; NIHR BioResource for Translational Research &amp; Addenbrooke\u2019s Hospital NHS Foundation Trust &amp; Royal Papworth Hospital NHS Foundation Trust, Cambridge CB2 0QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geert","family":"van Loo","sequence":"additional","affiliation":[{"name":"VIB Center for Inflammation Research, 9052 Ghent, Belgium"},{"name":"Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9699-4860","authenticated-orcid":false,"given":"Jan H.","family":"von der Th\u00fcsen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Erasmus MC, University Medical Center Rotterdam, 3015 GE Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7223-4565","authenticated-orcid":false,"given":"Thierry P. P.","family":"van den Bosch","sequence":"additional","affiliation":[{"name":"Department of Pathology, Erasmus MC, University Medical Center Rotterdam, 3015 GE Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria-Rosa","family":"Ghigna","sequence":"additional","affiliation":[{"name":"School of Medicine, Universit\u00e9 Paris-Saclay, 94270 Le Kremlin-Bic\u00eatre, France"},{"name":"INSERM UMR_S 999, Pulmonary Hypertension: Pathology and Novel Therapies, H\u00f4pital Marie Lannelongue, 92350 Le Plessis Robinson, France"},{"name":"Division of Pathology, Marie Lannelongue Hospital, 92350 Le Plessis Robinson, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7730-2427","authenticated-orcid":false,"given":"Fr\u00e9d\u00e9ric","family":"Perros","sequence":"additional","affiliation":[{"name":"School of Medicine, Universit\u00e9 Paris-Saclay, 94270 Le Kremlin-Bic\u00eatre, France"},{"name":"INSERM UMR_S 999, Pulmonary Hypertension: Pathology and Novel Therapies, H\u00f4pital Marie Lannelongue, 92350 Le Plessis Robinson, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9358-6922","authenticated-orcid":false,"given":"David","family":"Montani","sequence":"additional","affiliation":[{"name":"School of Medicine, Universit\u00e9 Paris-Saclay, 94270 Le Kremlin-Bic\u00eatre, France"},{"name":"INSERM UMR_S 999, Pulmonary Hypertension: Pathology and Novel Therapies, H\u00f4pital Marie Lannelongue, 92350 Le Plessis Robinson, France"},{"name":"Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Assistance Publique\u2014H\u00f4pitaux de Paris (AP-HP), H\u00f4pital Bic\u00eatre, 94270 Le Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirjam","family":"Kool","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1519-8147","authenticated-orcid":false,"given":"Karin A.","family":"Boomars","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudi W.","family":"Hendriks","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1801913","DOI":"10.1183\/13993003.01913-2018","article-title":"Haemodynamic definitions and updated clinical classification of pulmonary hypertension","volume":"53","author":"Simonneau","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/s41569-019-0242-x","article-title":"Molecular genetic framework underlying pulmonary arterial hypertension","volume":"17","author":"Southgate","year":"2020","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1801899","DOI":"10.1183\/13993003.01899-2018","article-title":"Genetics and genomics of pulmonary arterial hypertension","volume":"53","author":"Morrell","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1672","DOI":"10.1161\/01.CIR.0000012754.72951.3D","article-title":"Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor","volume":"105","author":"Atkinson","year":"2002","journal-title":"Circulation"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1002\/humu.22904","article-title":"Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects","volume":"36","author":"Machado","year":"2015","journal-title":"Hum. Mutat."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Andruska, A., and Spiekerkoetter, E. (2018). Consequences of BMPR2 Deficiency in the Pulmonary Vasculature and Beyond: Contributions to Pulmonary Arterial Hypertension. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19092499"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"L98","DOI":"10.1152\/ajplung.00252.2019","article-title":"Meta-analysis of blood genome-wide expression profiling studies in pulmonary arterial hypertension","volume":"318","author":"Elinoff","year":"2020","journal-title":"Am. J. Physiol. Cell. Mol. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"11409","DOI":"10.1111\/jcmm.15745","article-title":"Transcriptomic analysis identifies Toll-like and Nod-like pathways and necroptosis in pulmonary arterial hypertension","volume":"24","author":"Xiao","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Zhao, E., Xie, H., and Zhang, Y. (2021). Identification of Differentially Expressed Genes Associated with Idiopathic Pulmonary Arterial Hypertension by Integrated Bioinformatics Approaches. J. Comput. Biol.","DOI":"10.1089\/cmb.2019.0433"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Chesne, J., Danger, R., Botturi, K., Reynaud-Gaubert, M., Mussot, S., Stern, M., Danner-Boucher, I., Mornex, J.F., Pison, C., and Dromer, C. (2014). Systematic analysis of blood cell transcriptome in end-stage chronic respiratory diseases. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0109291"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1016\/j.bbrc.2012.08.106","article-title":"Viral Toll Like Receptor activation of pulmonary vascular smooth muscle cells results in endothelin-1 generation; relevance to pathogenesis of pulmonary arterial hypertension","volume":"426","author":"George","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/imm.12888","article-title":"Human dendritic cell subsets: An update","volume":"154","author":"Collin","year":"2018","journal-title":"Immunology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1586\/ers.11.17","article-title":"Viral infection and pulmonary hypertension: Is there an association?","volume":"5","author":"Cool","year":"2011","journal-title":"Expert Rev. Respir. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1504\/IJBRA.2014.065244","article-title":"Sequence-based prediction of linear autoepitopes involved in pathogenesis of IPAH and the corresponding organism sources of molecular mimicry","volume":"10","author":"Kubrycht","year":"2014","journal-title":"Int. J. Bioinform. Res. Appl."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1161\/CIRCULATIONAHA.109.933762","article-title":"Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension","volume":"122","author":"Soon","year":"2010","journal-title":"Circulation"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1161\/CIRCRESAHA.118.313911","article-title":"Discovery of Distinct Immune Phenotypes Using Machine Learning in Pulmonary Arterial Hypertension","volume":"124","author":"Sweatt","year":"2019","journal-title":"Circ. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1164\/rccm.201105-0927OC","article-title":"Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension","volume":"185","author":"Perros","year":"2012","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2339","DOI":"10.1084\/jem.20090410","article-title":"Dendritic cells are crucial for maintenance of tertiary lymphoid structures in the lung of influenza virus-infected mice","volume":"206","author":"GeurtsvanKessel","year":"2009","journal-title":"J. Exp. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2593","DOI":"10.1084\/jem.20091472","article-title":"Induced bronchus-associated lymphoid tissue serves as a general priming site for T cells and is maintained by dendritic cells","volume":"206","author":"Halle","year":"2009","journal-title":"J. Exp. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"11","DOI":"10.3389\/fimmu.2019.00011","article-title":"Dendritic Cell Subsets and Effector Function in Idiopathic and Connective Tissue Disease-Associated Pulmonary Arterial Hypertension","volume":"10","author":"Boomars","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1183\/09031936.00094706","article-title":"Dendritic cell recruitment in lesions of human and experimental pulmonary hypertension","volume":"29","author":"Perros","year":"2007","journal-title":"Eur. Respir. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1186\/1465-9921-12-119","article-title":"Increased oxidative stress and severe arterial remodeling induced by permanent high-flow challenge in experimental pulmonary hypertension","volume":"12","author":"Dorfmuller","year":"2011","journal-title":"Respir. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1161\/CIRCULATIONAHA.114.008750","article-title":"Endothelial-to-mesenchymal transition in pulmonary hypertension","volume":"131","author":"Ranchoux","year":"2015","journal-title":"Circulation"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1378\/chest.14-1678","article-title":"T-helper 17 cell polarization in pulmonary arterial hypertension","volume":"147","author":"Hautefort","year":"2015","journal-title":"Chest"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Marsh, L.M., Jandl, K., Grunig, G., Foris, V., Bashir, M., Ghanim, B., Klepetko, W., Olschewski, H., Olschewski, A., and Kwapiszewska, G. (2018). The inflammatory cell landscape in the lungs of patients with idiopathic pulmonary arterial hypertension. Eur. Respir. J., 51.","DOI":"10.1183\/13993003.01214-2017"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1007\/s10875-009-9322-8","article-title":"Impairment of monocyte-derived dendritic cells in idiopathic pulmonary arterial hypertension","volume":"29","author":"Wang","year":"2009","journal-title":"J. Clin. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1165\/rcmb.2019-0443OC","article-title":"DNGR1-Cre-mediated Deletion of Tnfaip3\/A20 in Conventional Dendritic Cells Induces Pulmonary Hypertension in Mice","volume":"63","author":"Koudstaal","year":"2020","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Koudstaal, T., Boomars, K.A., and Kool, M. (2020). Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: An Immunological Perspective. J. Clin. Med., 9.","DOI":"10.3390\/jcm9020561"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.immuni.2017.02.016","article-title":"Exposure to Bacterial CpG DNA Protects from Airway Allergic Inflammation by Expanding Regulatory Lung Interstitial Macrophages","volume":"46","author":"Sabatel","year":"2017","journal-title":"Immunity"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2045894018765840","DOI":"10.1177\/2045894018765840","article-title":"BMPR2 mutations and endothelial dysfunction in pulmonary arterial hypertension (2017 Grover Conference Series)","volume":"8","author":"Frump","year":"2018","journal-title":"Pulm. Circ."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1038\/nm.3877","article-title":"Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension","volume":"21","author":"Long","year":"2015","journal-title":"Nat. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1093\/cvr\/cvx159","article-title":"Role of cardiac inflammation in right ventricular failure","volume":"113","author":"Sun","year":"2017","journal-title":"Cardiovasc. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"604615","DOI":"10.1155\/2010\/604615","article-title":"Characteristics of interstitial fibrosis and inflammatory cell infiltration in right ventricles of systemic sclerosis-associated pulmonary arterial hypertension","volume":"2010","author":"Overbeek","year":"2010","journal-title":"Int. J. Rheumatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1038\/s41577-018-0065-8","article-title":"Cardioimmunology: The immune system in cardiac homeostasis and disease","volume":"18","author":"Swirski","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.coi.2020.09.005","article-title":"Exploring cardiac macrophage heterogeneity in the healthy and diseased myocardium","volume":"68","author":"Zaman","year":"2020","journal-title":"Curr. Opin. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e14532","DOI":"10.14814\/phy2.14532","article-title":"Adaptive and innate immune mechanisms in cardiac fibrosis complicating pulmonary arterial hypertension","volume":"8","author":"Siamwala","year":"2020","journal-title":"Physiol. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/nri3452","article-title":"Activation and regulation of the inflammasomes","volume":"13","author":"Latz","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.immuni.2014.12.031","article-title":"A20 restricts ubiquitination of pro-interleukin-1beta protein complexes and suppresses NLRP3 inflammasome activity","volume":"42","author":"Duong","year":"2015","journal-title":"Immunity"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/nature13322","article-title":"Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis","volume":"512","author":"Jacques","year":"2014","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"108381","DOI":"10.1016\/j.celrep.2020.108381","article-title":"Inflammasomes within Hyperactive Murine Dendritic Cells Stimulate Long-Lived T Cell-Mediated Anti-tumor Immunity","volume":"33","author":"Zhivaki","year":"2020","journal-title":"Cell Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5981","DOI":"10.4049\/jimmunol.1102868","article-title":"Lipopolysaccharide-activated dendritic cells: \"exhausted\" or alert and waiting?","volume":"188","author":"Abdi","year":"2012","journal-title":"J. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.pupt.2015.09.007","article-title":"Exploring the monocrotaline animal model for the study of pulmonary arterial hypertension: A network approach","volume":"35","author":"Vitorino","year":"2015","journal-title":"Pulm. Pharmacol. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1016\/j.cell.2013.07.014","article-title":"Genetic tracing via DNGR-1 expression history defines dendritic cells as a hematopoietic lineage","volume":"154","author":"Schraml","year":"2013","journal-title":"Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.1016\/j.jaci.2017.08.012","article-title":"TNF-alpha-induced protein 3 levels in lung dendritic cells instruct TH2 or TH17 cell differentiation in eosinophilic or neutrophilic asthma","volume":"141","author":"Vroman","year":"2018","journal-title":"J. Allergy Clin. Immunol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/4\/1756\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:22:23Z","timestamp":1760160143000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/4\/1756"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,10]]},"references-count":44,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["ijms22041756"],"URL":"https:\/\/doi.org\/10.3390\/ijms22041756","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,10]]}}}