Sema3E-plexinD1 axis regulates Foxp3+ Treg cells, mitigating allergic airway inflammation in asthma model

Asthma is a chronic inflammatory airway disease. Airway epithelial cells (AECs) are crucial for lung homeostasis, with Semaphorin3E (Sema3E) being a key AEC-derived factor. Its expression is often downregulated in severe asthmatics, suggesting a protective role. However, the precise mechanism by which AEC-derived Sema3E influences immune responses, particularly Foxp3+ regulatory T-cells (Tregs), in allergic asthma models remains underexplored. This study investigates the Sema3E-plexinD1 axis as a potential therapeutic target.

Researchers used a house dust mite (HDM) asthma model in mice. First, they generated tamoxifen-inducible Scgb1a1Cre transgenic mice to achieve AEC-specific Sema3E overexpression. They then assessed lung immune cell populations and BALF cytokines. Second, to pinpoint the role of plexinD1 in Tregs, they created cell-specific Foxp3-PLXND1 knockout (KO) mice and subjected them to HDM exposure, evaluating Treg numbers, eosinophil infiltration, T helper cell subsets, antibody levels, and airway remodeling markers.

Sema3E overexpression in AECs significantly increased lung Foxp3+ Treg cell number and proliferation, without altering other major immune cell populations or BALF cytokine levels.

In contrast, cell-specific Foxp3-PLXND1 knockout (KO) mice exhibited reduced Foxp3+ Treg cell numbers in the lungs, spleen, and mediastinal lymph nodes. This Treg reduction was accompanied by increased lung eosinophil infiltration, elevated IFN-γ+ CD4+ T cells in the spleen, and higher BALF levels of IL-17, IL-5, and CXCL8. Furthermore, Foxp3 PLXND1 deficiency enhanced the number of T follicular helper cells, germinal center B cells, and IgG1/IgE antibodies in sera. Airway remodeling markers were also elevated, with increased Muc5AC gene expression and goblet cell hyperplasia in KO mice.