Classical dendritic cells contribute to hypoxia‐induced pulmonary hypertension

Pulmonary hypertension (PH) is a chronic and progressive disease with significant morbidity and mortality. It is characterized by remodeled pulmonary vessels associated with perivascular and intravascular accumulation of inflammatory cells. Although there is compelling evidence that bone marrow-derived cells, such as macrophages and T cells, cluster in the vicinity of pulmonary vascular lesions in humans and contribute to PH development in different animal models, the role of dendritic cells in PH is less clear. Dendritic cells' involvement in PH is likely since they are responsible for coordinating innate and adaptive immune responses. We hypothesized that dendritic cells drive hypoxic PH. We demonstrate that a classical dendritic cell (cDC) subset (cDC2) is increased and activated in wild-type mouse lungs after hypoxia exposure. We observe significant protection after the depletion of cDCs in ZBTB46 DTR chimera mice before hypoxia exposure and after established hypoxic PH. In addition, we find that cDC depletion is associated with a reduced number of two macrophage subsets in the lung (FolR2<sup>+</sup> MHCII<sup>+</sup> CCR2<sup>+</sup> and FolR2<sup>+</sup> MHCII<sup>+</sup> CCR2<sup>-</sup>). We found that depleting cDC2s, but not cDC1s, was protective against hypoxic PH. Finally, proof-of-concept studies in human lungs show increased perivascular cDC2s in patients with Idiopathic Pulmonary Arterial Hypertension (IPAH). Our data points to an essential role of cDCs, particularly cDC2s, in the pathophysiology of experimental PH.

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Publication Details

Journal
The FASEB Journal
Published
2024-08-30
DOI
https://doi.org/10.1096/fj.202400338rr
Citations
11
Primary Topic
Immunotherapy and Immune Responses
Type
article
Field-Weighted Citation Impact
2.65

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article

Classical dendritic cells contribute to hypoxia‐induced pulmonary hypertension

Brian B. Graham, Tzu Phang, Kurt R. Stenmark, Rahul Kumar et al.
11 citations
The FASEB Journal
Immunotherapy and Immune Responses
2.65
article

Classical dendritic cells contribute to hypoxia‐induced pulmonary hypertension

Brian B. Graham, Tzu Phang, Kurt R. Stenmark, Rahul Kumar, David Irwin, Michael H. Lee, Linda Sanders, Amy S. McKee, Rubin M. Tuder, Kelly M. Cautivo, Sushil Kumar, Ari B. Molofsky, Claudia Mickael, Aneta Gandjeva, Robert S. Stearman, Delaney Swindle, Dara C. Fonseca‐Balladares, Biruk Kassa
article en
11 citations

Abstract

Pulmonary hypertension (PH) is a chronic and progressive disease with significant morbidity and mortality. It is characterized by remodeled pulmonary vessels associated with perivascular and intravascular accumulation of inflammatory cells. Although there is compelling evidence that bone marrow-derived cells, such as macrophages and T cells, cluster in the vicinity of pulmonary vascular lesions in humans and contribute to PH development in different animal models, the role of dendritic cells in PH is less clear. Dendritic cells' involvement in PH is likely since they are responsible for coordinating innate and adaptive immune responses. We hypothesized that dendritic cells drive hypoxic PH. We demonstrate that a classical dendritic cell (cDC) subset (cDC2) is increased and activated in wild-type mouse lungs after hypoxia exposure. We observe significant protection after the depletion of cDCs in ZBTB46 DTR chimera mice before hypoxia exposure and after established hypoxic PH. In addition, we find that cDC depletion is associated with a reduced number of two macrophage subsets in the lung (FolR2<sup>+</sup> MHCII<sup>+</sup> CCR2<sup>+</sup> and FolR2<sup>+</sup> MHCII<sup>+</sup> CCR2<sup>-</sup>). We found that depleting cDC2s, but not cDC1s, was protective against hypoxic PH. Finally, proof-of-concept studies in human lungs show increased perivascular cDC2s in patients with Idiopathic Pulmonary Arterial Hypertension (IPAH). Our data points to an essential role of cDCs, particularly cDC2s, in the pathophysiology of experimental PH.

The FASEB JournalVol. 38(16)
San Francisco General Hospital (US), University of California, San Francisco (US), Gilead Sciences (United States) (US), Indiana University School of Medicine, University of Colorado Anschutz Medical Campus (US), Indiana University – Purdue University Indianapolis (US), University of Colorado Denver (US)
U.S. Department of Defense, American Heart Association, American Thoracic Society, United Therapeutics Corporation, Cardiovascular Medical Research and Education Fund, National Institutes of Health, National Heart, Lung, and Blood Institute, Actelion Pharmaceuticals
Good health and well-being
Openalex Percentile: Top 10%
Immunotherapy and Immune Responses
2.65
DOIOpen Access PDFOpenAlex
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