2. Academic Validation
  3. NLRP3 regulates ferroptosis via the JAK2/STAT3 pathway in asthma inflammation: Insights from in vivo and in vitro studies

NLRP3 regulates ferroptosis via the JAK2/STAT3 pathway in asthma inflammation: Insights from in vivo and in vitro studies

  • Int Immunopharmacol. 2024 Dec 25;143(Pt 2):113416. doi: 10.1016/j.intimp.2024.113416.
Zhengze Zhang 1,  Yuewen He 1,  Hao Liu 2,  Yurui Liu 1,  Tong Wu 1,  Ruogen Li 3,  Yong Wang 4,  Wuhua Ma 5
Affiliations

Affiliations

  • 1 The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China; Department of Anesthesiology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China.
  • 2 The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China; Department of Anesthesiology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China.
  • 3 The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China.
  • 4 Department of Anesthesiology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China; State Key Laboratory of Traditional Chinese Medicine Syndrome, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China. Electronic address: yongwang@outlook.com.
  • 5 Department of Anesthesiology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China. Electronic address: tuesdaymorninggz@126.com.
PMID: 39426227 DOI: 10.1016/j.intimp.2024.113416
Abstract

Background: Ferroptosis, an iron-dependent form of cell death, plays a pivotal role in the pathologic progression of asthma. Electroacupuncture (EA) has demonstrated considerable efficacy in mitigating asthma airway inflammation, although its underlying mechanisms remain partially elucidated.

Methods: We investigated the regulatory effect of NLRP3 on Ferroptosis using a lipopolysaccharide (LPS)-induced inflammation model in BEAS-2B cells, where NLRP3 expression was modulated with si-RNA and overexpression plasmids. The levels of inflammatory cytokines TNF-α, IL-1β, and IL-6 were quantified. We also assessed NLRP3 and JAK2/STAT3 pathway-related proteins, and evaluated lipid peroxidation, mitochondrial membrane potential (ΔΨm), and antioxidant system functionality. In vivo, we examined the impact of EA on Ferroptosis and airway inflammation by modulating NLRP3 activation. Asthma inflammation severity was evaluated using H&E, Masson, and PAS staining, alongside ELISA. NLRP3 and JAK2/STAT3 pathway-related proteins, as well as Ferroptosis indicators, were also analyzed. The mechanism by which NLRP3 activates Ferroptosis was investigated through in vitro assays.

Results: LPS exposure resulted in increased intracellular inflammatory cytokines, and activation of the NLRP3 and JAK2/STAT3 pathways, leading to enhanced lipid peroxidation, decreased ΔΨm, and disruption of antioxidant system balance, ultimately inducing Ferroptosis. Si-NLRP3 countered the effects of LPS, whereas oe-NLRP3 exacerbated symptoms. In vivo studies revealed that EA reduced airway inflammation, inhibited NLRP3 activation, and decreased phosphorylation of JAK2/STAT3, effectively lowering ferroptosis-related indicators. Utilizing JAK2/STAT3 activators and inhibitors, we confirmed that NLRP3 mediates Ferroptosis via the JAK2/STAT3 pathway.

Conclusions: EA alleviates HDM-induced asthma, primarily through the inhibition of NLRP3 activation, which modulates the JAK2/STAT3 pathway and mediates Ferroptosis.

Keywords

Asthma; Electroacupuncture; Ferroptosis; JAK2/STAT3 pathway; NLRP3.

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