Signaling roles of ceramide and its metabolites in cutaneous antimicrobial defense

The skin epidermis is a multipurpose barrier (i.e., against epidermal permeability disruption and oxidative/UV irradiation) as well as a mechanical barrier and antimicrobial barrier, to protect cells/tissues from external perturbants. When there is a normal barrier, function is restored and/or enhanced in the epidermis in response to external perturbations. Ceramide (Cer) is a well-known, key lipid constituent of the epidermal permeability barrier in the extracellular domain of the stratum corneum. Cer and its metabolites also serve as signaling lipids to regulate cellular function (e.g., proliferation, differentiation, and apoptosis). Recent studies from our laboratory demonstrate that the Cer metabolites, sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P), generate signaling transcriptionally to stimulate cathelicidin antimicrobial peptide (CAMP), and human beta-defensin (hBD) 2 and hBD3 production, respectively, in cells, including in epidermal keratinocytes. S1P and C1P production are increased by external perturbation-induced endoplasmic reticulum stress. These studies illuminate a mechanism through which external perturbations signal to stimulate antimicrobial peptides without evidence of microbial infections. In this work, we describe the signaling roles of Cer, S1P, and C1P in cells