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Background <p>Airway epithelial damage is a pathologic feature commonly observed in the individuals with asthma, and it primarily triggers bronchial hyperresponsiveness and airway remodeling. The present study aimed to investigate the protective effect of Netrin-1 against asthmatic airway inflammation by modulating the NLRP3 inflammasome.</p> Methods <p>Lentiviral transfection was performed to regulate Netrin-1 expression in house dust mite (HDM)-induced human airway epithelial cells and a murine&#xa0;asthma model. ROS levels and cell apoptosis were quantified via flow cytometry. The levels of inflammatory cytokines were assessed using ELISA. The expression of NLRP3 inflammasome components&#xa0;and activation of the&#xa0;HMGB1/RAGE/NF-κB axis were&#xa0;examined via qRT-PCR and Western blotting. The protective effects of Netrin-1 overexpression on asthmatic mice was assessed by HE, PAS and immunohistochemical staining.</p> Results <p>Netrin-1&#xa0;overexpression notably inhibited cell apoptosis, while decreasing the level of ROS and the proinflammatory cytokines&#xa0;including IL-4, IL-6, and IL-13. These effects were associated with modulation of the HMGB1/RAGE/NF-κB pathway and attenuation of the NLRP3 inflammasome response. In asthmatic mice, Netrin-1 activation significantly reduced airway inflammation and mucus hypersecretion. Conversely, co-overexpression of HMGB1 or administration of the NLRP3 activator abolished these protective effects, underscoring the complex interaction between these molecules.</p> Conclusions <p>Netrin-1 exerts anti-inflammatory effect&#xa0;by inhibiting the NLRP3 inflammasome activation and suppressing HMGB1/RAGE/NF-κB signaling pathway&#xa0;activation. Our preliminary findings demonstrate that Netrin-1&#xa0;may serve as a potential therapeutic target for asthma, offering novel insights into its pathogenic mechanisms.</p> Graphical Abstract <p></p>

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Netrin-1 as an asthma suppressor to inhibit NLRP3 inflammasome and asthmatic airway inflammation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月11日

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  • Wei Zhou,
  • Ying Tian,
  • Zhen Guo,
  • Mingxia Li

摘要

Background

Airway epithelial damage is a pathologic feature commonly observed in the individuals with asthma, and it primarily triggers bronchial hyperresponsiveness and airway remodeling. The present study aimed to investigate the protective effect of Netrin-1 against asthmatic airway inflammation by modulating the NLRP3 inflammasome.

Methods

Lentiviral transfection was performed to regulate Netrin-1 expression in house dust mite (HDM)-induced human airway epithelial cells and a murine asthma model. ROS levels and cell apoptosis were quantified via flow cytometry. The levels of inflammatory cytokines were assessed using ELISA. The expression of NLRP3 inflammasome components and activation of the HMGB1/RAGE/NF-κB axis were examined via qRT-PCR and Western blotting. The protective effects of Netrin-1 overexpression on asthmatic mice was assessed by HE, PAS and immunohistochemical staining.

Results

Netrin-1 overexpression notably inhibited cell apoptosis, while decreasing the level of ROS and the proinflammatory cytokines including IL-4, IL-6, and IL-13. These effects were associated with modulation of the HMGB1/RAGE/NF-κB pathway and attenuation of the NLRP3 inflammasome response. In asthmatic mice, Netrin-1 activation significantly reduced airway inflammation and mucus hypersecretion. Conversely, co-overexpression of HMGB1 or administration of the NLRP3 activator abolished these protective effects, underscoring the complex interaction between these molecules.

Conclusions

Netrin-1 exerts anti-inflammatory effect by inhibiting the NLRP3 inflammasome activation and suppressing HMGB1/RAGE/NF-κB signaling pathway activation. Our preliminary findings demonstrate that Netrin-1 may serve as a potential therapeutic target for asthma, offering novel insights into its pathogenic mechanisms.

Graphical Abstract