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Cullin5 drives experimental asthma exacerbations by modulating alveolar macrophage antiviral immunity

Haibo Zhang1,2,3, Keke Xue1,2,3, Wen Li1,2,3

  • 1Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, 200240, Shanghai, P. R. China.

Nature Communications
|January 4, 2024
PubMed

Insights

Asthma exacerbations linked to viral infections worsen with higher Cullin5 (CUL5) levels. Reducing CUL5 boosts antiviral immunity, mitigating lung inflammation and asthma severity in mouse models.

Area of Science:

  • Immunology
  • Molecular Biology
  • Respiratory Medicine

Background:

  • Asthma exacerbations are frequently triggered by viral infections, posing a significant global health challenge.
  • The precise mechanisms linking impaired antiviral immunity to asthma pathogenesis remain incompletely understood.
  • Cullin5 (CUL5) is a component of the Cullin-RING E3 ubiquitin ligase complex, implicated in protein ubiquitination and degradation.

Purpose of the Study:

  • To investigate the role of Cullin5 (CUL5) in the pathogenesis of viral-induced asthma exacerbations.
  • To elucidate the molecular mechanisms by which CUL5 influences antiviral immunity and lung inflammation in asthma.
  • To explore the therapeutic potential of targeting the CUL5 signaling pathway for asthma treatment.

Main Methods:

  • Utilized mouse models of house dust mite-induced asthma and influenza infection.
  • Assessed the expression levels of Cullin5 (CUL5) in lung tissues.
  • Investigated the interaction between CUL5 and O-GlcNAc transferase (OGT) following thymic stromal lymphopoietin stimulation.
  • Measured IFN-β production, neutrophil counts, and RIG-I signaling activation.

Main Results:

  • Cullin5 (CUL5) expression was upregulated in asthma exacerbation models, correlating with increased neutrophil counts and disease severity.
  • CUL5 deficiency led to reduced neutrophilic lung inflammation and mitigated asthma exacerbations.
  • CUL5 deficiency enhanced interferon-beta (IFN-β) production, indicating improved antiviral responses.
  • Mechanistically, CUL5 was found to interact with OGT, promoting OGT polyubiquitination and inhibiting O-GlcNAcylation and RIG-I signaling.

Conclusions:

  • Pre-existing allergic injury in mouse models upregulates CUL5, which impairs antiviral immunity and promotes neutrophilic inflammation, leading to asthma exacerbations.
  • The CUL5/OGT interaction plays a critical role in suppressing antiviral responses during asthma.
  • Targeting the CUL5/IFN-β signaling axis presents a potential therapeutic strategy for managing viral-induced asthma exacerbations.

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