Role of the Notch ligands Jagged1 and Delta4 in Th17/Treg immune imbalance in a mouse model of chronic asthma

Abstract

Purpose

Asthma is associated with a T helper (Th)17/regulatory T (Treg) cells immune imbalance where the Notch signaling pathway contributes vitally. This study aimed to explore the role of Notch ligands Jagged1 and Delta4 in the Th17/Treg immune imbalance of chronic asthmatic mice.

Methods

The experimental animals were randomly assigned to the Saline, ovalbumin (OVA), and OVA + γ-secretase inhibitor (GSI) groups. A mouse model of chronic asthma was induced by OVA sensitization and challenge. GSI was injected intraperitoneally before the OVA challenge in the OVA + GSI group. Lung function, lung histopathology and immunohistochemistry to assess airway inflammation, enzyme-linked immunosorbent assay to measure cytokines levels, flow cytometry to measure the proportions of Th17 (Th17%) and Treg% in CD4⁺T cells, quantitative real-time polymerase chain reaction and western blot to measure mRNA and protein levels of Jagged1 and Delta4 in lung tissue, and correlation analysis were performed.

Results

Lung function and histopathology and IL-4, IL-13, and IFN-γ levels in the bronchoalveolar lavage fluid (BALF) of chronic asthmatic mice showed characteristic changes of asthma. The Th17%, Th17/Treg ratio, BALF and serum IL-17 levels, and IL-17/IL-10 ratio increased significantly in the OVA group, while the Treg% and IL-10 level significantly decreased. mRNA and protein expression levels of Jagged1 and Delta4 increased significantly. GSI could reduce the Th17%, Th17/Treg ratio, IL-17, IL-17/IL-10 ratio, and Jagged1 expression in chronic asthmatic mice. The mRNA and protein levels of Jagged1 and Delta4 were positively correlated with the Th17/Treg ratio in the OVA group, while only those of Jagged1 were positively correlated with the Th17/Treg ratio in the OVA + GSI group.

Conclusions

In chronic asthmatic mice, the Th17/Treg ratio increased, and the Notch ligands Jagged1 and Delta4 were overactive and positively regulated the Th17/Treg imbalance. GSI partially inhibited Jagged1 and relieved the Th17/Treg imbalance.

Keywords:

• Asthma
• Jagged1
• Delta4
• Th17
• Treg

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Key Research and Development Program of Gansu Province of China under Grant 17YF1FA129.