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Background <p>Alveolar macrophages (AMs) are crucial for defending against respiratory syncytial virus (RSV) and regulating lung inflammation. Notch signaling is essential for macrophage polarization and its functional diversity.However, the role of macrophages Notch1 in RSV-induced lung injury and its underlying mechanisms remain incompletely understood. </p> Methods <p>This study used macrophage-specific Notch1 knockout (MKO) mice to investigate the lung lesions and inflammation in RSV-infected mice. The effects of various interventions, including JAG1, Nr1d1 inhibitor, and Bnip3 gene manipulation, were assessed in RSV-infected mice. Western blot (WB) was used to measure the expression of inflammasome-related proteins, such as NLR family, pyrin domain containing 3 (Nlrp3), Asc, Cleaved-caspase1, and nuclear receptor subfamily 1, group D, member 1 (Nr1d1), BCL2/adenovirus E1B 19&#xa0;kDa interacting protein 3 ‌(Bnip3) in lung or macrophages. Additionally, RNA sequencing (RNA-seq) of macrophages from RSV-infected mice was performed to identify differential gene expression between MKO and wild-type (Flox) mice. Confocal microscopy visualized the localization of autophagy complexes in cellular mitochondria. ELISA assays measured LDH, IL-1β and IL-18 levels in bronchoalveolar lavage fluid (BALF).</p> Results <p>Compared to Flox mice, MKO mice showed milder lung lesions, increased Nr1d1 and Bnip3 expression, and decreased Nlrp3 inflammasome activity in RSV-exposed mice. Moreover, Nr1d1 inhibitor reduced Bnip3 expression, increased IL-1β and IL-18 release, and exacerbated pulmonary inflammation. Inhibiting Bnip3 exacerbated RSV-induced lung injury by enhancing Nlrp3 inflammasome activity and impairing mitophagy.</p> Conclusion <p>These results suggest that Notch signaling regulates Nr1d1/Bnip3-induced mitophagy, influencing the Nlrp3 inflammasome and the inflammatory response during RSV infection.</p>

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Suppression of Nr1d1/Bnip3-dependent mitophagy by notch signaling aggravates inflammatory response in RSV-infected mice lungs

  • 期刊论文

  • 发表日期：

    2026年4月10日

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  • Yuxi Lei,
  • Zhi Liu,
  • Hui Du,
  • Ruiyu Zhang,
  • Huizhi Hu,
  • Pu Yang,
  • Junwen Zheng,
  • Dongchi Zhao

摘要

Background

Alveolar macrophages (AMs) are crucial for defending against respiratory syncytial virus (RSV) and regulating lung inflammation. Notch signaling is essential for macrophage polarization and its functional diversity.However, the role of macrophages Notch1 in RSV-induced lung injury and its underlying mechanisms remain incompletely understood.

Methods

This study used macrophage-specific Notch1 knockout (MKO) mice to investigate the lung lesions and inflammation in RSV-infected mice. The effects of various interventions, including JAG1, Nr1d1 inhibitor, and Bnip3 gene manipulation, were assessed in RSV-infected mice. Western blot (WB) was used to measure the expression of inflammasome-related proteins, such as NLR family, pyrin domain containing 3 (Nlrp3), Asc, Cleaved-caspase1, and nuclear receptor subfamily 1, group D, member 1 (Nr1d1), BCL2/adenovirus E1B 19 kDa interacting protein 3 ‌(Bnip3) in lung or macrophages. Additionally, RNA sequencing (RNA-seq) of macrophages from RSV-infected mice was performed to identify differential gene expression between MKO and wild-type (Flox) mice. Confocal microscopy visualized the localization of autophagy complexes in cellular mitochondria. ELISA assays measured LDH, IL-1β and IL-18 levels in bronchoalveolar lavage fluid (BALF).

Results

Compared to Flox mice, MKO mice showed milder lung lesions, increased Nr1d1 and Bnip3 expression, and decreased Nlrp3 inflammasome activity in RSV-exposed mice. Moreover, Nr1d1 inhibitor reduced Bnip3 expression, increased IL-1β and IL-18 release, and exacerbated pulmonary inflammation. Inhibiting Bnip3 exacerbated RSV-induced lung injury by enhancing Nlrp3 inflammasome activity and impairing mitophagy.

Conclusion

These results suggest that Notch signaling regulates Nr1d1/Bnip3-induced mitophagy, influencing the Nlrp3 inflammasome and the inflammatory response during RSV infection.