Mast cells and sphingosine-1-phosphate underlie prelesional remodeling in a mouse model of eczema.

Abstract

Atopic dermatitis (AD) is a chronic skin inflammation that affects children and adults worldwide, but its pathogenesis remains ill-understood. We show that a single application of OVA to mouse skin initiates remodeling and cellular infiltration of the hypodermis measured by a newly developed computer-aided method. Importantly, we demonstrate that skin mast cell (MC) activation and local sphingosine-1-phosphate (S1P) are significantly augmented after OVA treatment in mice. Deficiency in sphingosine kinase (SphK)1, the S1P-producing enzyme, or in MC, remarkably mitigates all signs of OVA-mediated remodeling and MC activation. Furthermore, skin S1P levels remain unchanged in MC-deficient mice exposed to OVA. LPS-free OVA does not recapitulate any of the precursor signs of AD, supporting a triggering contribution of LPS in AD that, per se, suffice to activate local MC and elevate skin S1P. We describe MC and S1P as novel pathogenic effectors that initiate remodeling in AD prior to any skin lesions and reveal the significance of LPS in OVA used in most studies, thus mimicking natural antigen (Ag) exposure.