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

Cell Cycle. 2022 Oct;21(20):2179-2191. doi: 10.1080/15384101.2022.2092166. Epub 2022 Jun 26.

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 models in vitro and in vivo. 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.

Keywords: Substance P; bronchial asthma; inflammatory factors; pyroptotic cell death.

MeSH terms

  • Animals
  • Asthma*
  • Carrier Proteins
  • Caspase 1 / metabolism
  • Epithelial Cells / metabolism
  • Humans
  • Inflammasomes / metabolism
  • Inflammation / pathology
  • Interleukin-18 / metabolism
  • Lactate Dehydrogenases / metabolism
  • Leukocytes, Mononuclear / metabolism
  • Mice
  • NF-kappa B* / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyroptosis
  • Receptors, Neurokinin-1 / metabolism*
  • Substance P / metabolism*

Substances

  • Carrier Proteins
  • Inflammasomes
  • Interleukin-18
  • NF-kappa B
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Receptors, Neurokinin-1
  • Substance P
  • Lactate Dehydrogenases
  • Proto-Oncogene Proteins c-akt
  • Caspase 1

Grants and funding

The author(s) reported there is no funding associated with the work featured in this article.