Interleukin (IL)-33, known to be increased in eosinophilic asthma and suggested as a therapeutic target for it, activates endothelial cells in which Sry-related high-mobility-group box (Sox) 17, an endothelial-specific transcription factor, was upregulated.
We investigated the relationship between Sox17 and IL-33, and the possible role of Sox17 in the pathogenesis of asthma using a mouse model of airway inflammation.
We used ovalbumin (OVA) to induce airway inflammation in endothelium-specific Sox17 null mutant mice, and utilized IL-33 neutralizing antibody to evaluate the interplay between IL-33 and Sox17. We evaluated the airway inflammation, measured the levels of various cytokines, chemokines, and adhesion molecules. We also carried out loss- or gain-of-function experiments for Sox17 in human endothelial cells.
The levels of IL-33 and Sox17 expression were significantly increased in the lungs of OVA-challenged mice. Anti-IL-33 neutralizing antibody treatment attenuated not only OVA-induced airway inflammation but also Sox17 expression in pulmonary endothelial cells. Importantly, endothelium-specific deletion of Sox17 resulted in significant alleviation of various clinical features of asthma, including airway inflammation, immune cell infiltration, cytokine/chemokine production, and airway hyperresponsiveness. Sox17 deletion also resulted in decreased densities of Ly6chigh monocytes and inflammatory DCs in the lungs. In IL-33-stimulated human endothelial cells, Sox17 showed positive correlation with CCL2 and ICAM-1. Lastly, Sox17 promoted monocytes adhesion to endothelial cells, and upregulated the ERK-STAT3 pathway.
Sox17 was regulated by IL-33, and its genetic ablation in endothelial cells resulted in alleviation of asthma-related pathophysiologic features. Sox17 may be a potential target for asthma management.
Keywords : Sox17; IL-33; asthma; allergic airway inflammation