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| Status |
Public on Apr 12, 2024 |
| Title |
IL-6/gp130 signaling in CD4+ T cells drives the pathogenesis of pulmonary hypertension |
| Organisms |
Mus musculus; Rattus norvegicus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Pulmonary arterial hypertension (PAH) is characterized by stenosis and occlusions of small pulmonary arteries, leading to elevated pulmonary arterial pressure and right heart failure. Although accumulating evidence shows the importance of interleukin (IL)-6 in the pathogenesis of PAH, the target cells of IL-6 are poorly understood. Using mice harboring the floxed allele of gp130, a subunit of IL-6 receptor, we found substantial Cre recombination in all hematopoietic cell lineages from the primitive hematopoietic stem cell level in SM22α-Cre mice. We also revealed that a CD4+ cell-specific gp130 deletion ameliorated the phenotype of hypoxia-induced pulmonary hypertension in mice. Disruption of IL-6 signaling via deletion of gp130 in CD4+ T cells inhibited phosphorylation of signal transducer and activator of transcription 3 (STAT3) and suppressed the hypoxia-induced increase in T helper 17 cells. To further examine the role of IL-6/gp130 signaling in more severe PH models, we developed Il6 knockout (KO) rats using the CRISPR/Cas9 system and showed that IL-6 deficiency could improve the pathophysiology in hypoxia-, monocrotaline-, and Sugen5416/hypoxia (SuHx)-induced rat PH models. Phosphorylation of STAT3 in CD4+ cells was also observed around the vascular lesions in the lungs of SuHx rat model, but not in Il6 KO rats. Blockade of IL-6 signaling had an additive effect on conventional PAH therapeutics, such as endothelin receptor antagonist (macitentan) and soluble guanylyl cyclase stimulator (BAY41-2272). These findings suggest that IL-6/gp130 signaling in CD4+ cells plays a critical role in the pathogenesis of PAH.
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| Overall design |
mRNA profiles of total lung tissue and CD4-positive cells of wild type (WT) and IL6-/- SuHx rats, and of CD4-positive cells of splenocytes from Ai14;SM22alpha-Cre mice
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| Web link |
https://doi.org/10.1073/pnas.2315123121
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| Contributor(s) |
Ishibashi T, Inagaki T, Okazawa M, Shirai M, Nakaoka Y |
| Citation(s) |
38602915 |
| |
| Submission date |
Feb 16, 2024 |
| Last update date |
Apr 12, 2024 |
| Contact name |
Tadakatsu Inagaki |
| E-mail(s) |
inagaki.tadakatsu@ncvc.go.jp
|
| Organization name |
National Cerebral and Cardiovascular Center
|
| Department |
Vascular Physiology
|
| Street address |
6-1, Kishibesinnmachi
|
| City |
Suita |
| State/province |
Osaka |
| ZIP/Postal code |
564-8565 |
| Country |
Japan |
| |
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| Platforms (2) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
| GPL20084 |
Illumina NextSeq 500 (Rattus norvegicus) |
|
| Samples (22)
|
| GSM8083915 |
Total Lung Tissue IL6KO SuHx 56d 1 |
| GSM8083916 |
Total Lung Tissue IL6KO SuHx 56d 2 |
| GSM8083917 |
Total Lung Tissue IL6KO SuHx 56d 3 |
| GSM8083918 |
Total Lung Tissue WT SuHx 7d 1 |
| GSM8083919 |
Total Lung Tissue WT SuHx 7d 2 |
| GSM8083920 |
Total Lung Tissue WT SuHx 7d 3 |
| GSM8083921 |
Total Lung Tissue IL6KO SuHx 7d 1 |
| GSM8083922 |
Total Lung Tissue IL6KO SuHx 7d 2 |
| GSM8083923 |
Total Lung Tissue IL6KO SuHx 7d 3 |
| GSM8083924 |
Lung CD4-positive cell WT SuHx 7d 1 |
| GSM8083925 |
Lung CD4-positive cell WT SuHx 7d 2 |
| GSM8083926 |
Lung CD4-positive cell IL6KO SuHx 7d 1 |
| GSM8083927 |
Lung CD4-positive cell IL6KO SuHx 7d 2 |
| GSM8083928 |
tdTomato-positive CD4-positive cell from splenocytes of SM22alpha-Cre reporter mouse 1 |
| GSM8083929 |
tdTomato-positive CD4-positive cell from splenocytes of SM22alpha-Cre reporter mouse 2 |
| GSM8083930 |
tdTomato-positive CD4-positive cell from splenocytes of SM22alpha-Cre reporter mouse 3 |
| GSM8083931 |
tdTomato-negative CD4-positive cell from splenocytes of SM22alpha-Cre reporter mouse 1 |
| GSM8083932 |
tdTomato-negative CD4-positive cell from splenocytes of SM22alpha-Cre reporter mouse 2 |
| GSM8083933 |
tdTomato-negative CD4-positive cell from splenocytes of SM22alpha-Cre reporter mouse 3 |
|
| Relations |
| BioProject |
PRJNA1077362 |
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