MFG-E8/integrin β3 signaling contributes to airway inflammation response and airway remodeling in an ovalbumin-induced murine model of asthma.

Abstract

Asthma is the most common chronic childhood disease worldwide, characterized by airway remodeling and chronic inflammation, orchestrated primarily by Th2 cytokines. The aim of the current study was to explore the influences of milk fat globule epidermal growth factor 8 (MFG-E8)/integrin β3 signaling involved in airway inflammation and remodeling in asthma. BALB/c mice were sensitized by intraperitoneal injection of ovalbumin (OVA), followed by OVA nebulization. The levels of MFG-E8 expression were declined markedly in the OVA-induced allergy murine model. In addition, administration of MFG-E8 strongly reduced the accumulation of T-helper type 2 (Th2)-associated cytokines (such as interleukin-4, -5, and -13) as well as chemokine CCL11 (eotaxin) in bronchoalveolar lavagefluid and tissues in the OVA-sensitized mice. Moreover, MFG-E8 remarkably repressed the total immunoglobulin Eand OVA-specific immunoglobulin E in serum in OVA-challenged mice. Meanwhile, treatment with recombinant murine MFG-E8 noticeably prevented inflammatory cell infiltration into the airways, as showed by a marked decrease in the numbers of total immune cells, eosinophils, neutrophils, macrophages, and lymphocytes in the bronchoalveolar lavage fluid in response to OVA challenge. Importantly, MFG-E8 apparently alleviated OVA-driven airway remodeling, which were evidenced by declined secretion of important mediators of airway remodeling, including transforming growth factor-β1, matrix metalloproteinase 9, ADAM8, and vascular endothelial growth factor, and reduced airway collagen deposition and inhibited goblet cell hyperplasia in OVA-induced asthma in mice. Mechanistically, integrin 3 contributes to the protective effect of MFG-E8 in inhibiting airway inflammation and remodeling in OVA-driven features of allergic asthma. Overall, MFG-E8, as a candidate molecule to evaluate airway inflammation and remodeling, could be a potential target for the management and prevention of asthma exacerbations, suggesting that MFG-E8/integrin β3 signaling may serve as a promising therapeutic agent for childhood asthma.