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Substance P promotes the progression of bronchial asthma through activating the PI3K/AKT/NF-κB pathway mediated cellular inflammation and pyroptotic cell death in bronchial epithelial cells
- Source :
- Cell Cycle
- Publication Year :
- 2022
- Publisher :
- Taylor & Francis, 2022.
-
Abstract
- NOD-like receptor family pyrin domain containing three (NLRP3) inflammasome-mediated pyroptotic cell death and inflammation contribute to the pathogenesis of bronchial asthma, and it is reported that Substance P (SP) plays important role in the process, however, the detailed molecular mechanisms by which SP participates in the aggravation of bronchial asthma have not been fully studied. Here, our clinical data showed that SP and its receptor Neurokinin-1 receptor (NK1R) were significantly elevated in the plasma and peripheral blood mononuclear cell (PBMC) collected from patients with bronchial asthma, and further pre-clinical experiments evidenced that SP suppressed cell viability, accelerated lactate dehydrogenase (LDH) release, and upregulated ASC, Caspase-1, NLRP3, IL-1β and IL-18 to promote pyroptotic cell death and cellular inflammation in the human bronchial epithelial cells and asthmatic mice modelsiin vitro/iandiin vivo/i. Interestingly, SP-induced pyroptotic cell death was reversed by NK1R inhibitor L732138. Then, we uncovered the underlying mechanisms, and found that SP activated the downstream PI3K/AKT/NF-κB signal pathway in a NK1R-dependent manner, and blockage of this pathway by both PI3K inhibitor (LY294002) and NF-κB inhibitor (MG132) reversed SP-induced pyroptotic cell death and recovered cell viability in bronchial epithelial cells. Collectively, we concluded that SP interacted with its receptor NK1R to activate the PI3K/AKT/NF-κB pathway, which further triggered NLRP3-mediated pyroptotic cell death in the bronchial epithelial cells, resulting in the aggravation of bronchial asthma.
- Subjects :
- Inflammation
Inflammasomes
Caspase 1
Interleukin-18
NF-kappa B
Epithelial Cells
Cell Biology
Receptors, Neurokinin-1
Substance P
Asthma
Mice
Phosphatidylinositol 3-Kinases
NLR Family, Pyrin Domain-Containing 3 Protein
Leukocytes, Mononuclear
Pyroptosis
Animals
Humans
Carrier Proteins
Molecular Biology
Lactate Dehydrogenases
Proto-Oncogene Proteins c-akt
Developmental Biology
Research Paper
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Cell Cycle
- Accession number :
- edsair.doi.dedup.....95a0aba9807027fac1db55f296ef176f