Co-Regulation and Interdependence of the Mammalian Epidermal Permeability and Antimicrobial Barriers

Abstract

Human epidermis elaborates two small cationic, highly hydrophobic antimicrobial peptides (AMP), beta-defensin 2 (hBD2), and the carboxypeptide cleavage product of human cathelicidin (hCAP18), LL-37, which are co-packaged along with lipids within epidermal lamellar bodies (LBs) before their secretion. Because of their colocalization, we hypothesized that AMP and barrier lipid production could be coregulated by altered permeability barrier requirements. mRNA and immunostainable protein levels for mBD3 and cathelin-related antimicrobial peptide (CRAMP) (murine homologues of hBD2 and LL-37, respectively) increase 1-8 hours after acute permeability barrier disruption and normalize by 24 hours, kinetics that mirror the lipid metabolic response to permeability barrier disruption. Artificial permeability barrier restoration, which inhibits the lipid-synthetic response leading to barrier recovery, blocks the increase in AMP mRNA/protein expression, further evidence that AMP expression is linked to permeability barrier function. Conversely, LB-derived AMPs are also important for permeability barrier homeostasis. Despite an apparent increase in mBD3 protein, CRAMP-/- mice delayed permeability barrier recovery, attributable to defective LB contents and abnormalities in the structure of the lamellar membranes that regulate permeability barrier function. These studies demonstrate that (1) the permeability and antimicrobial barriers are coordinately regulated by permeability barrier requirements and (2) CRAMP is required for permeability barrier homeostasis.

Therapeutic Implications of a Barrier-based Pathogenesis of Atopic Dermatitis

“…Together, these observations point to loss of a competent antimicrobial barrier in AD. While failure of both permeability and antimicrobial function is wellrecognized in AD, only recently has it become clear that these 2 functions share common structural and biochemical features 11 , and both are co-regulated and interdependent 65 (Table 1). Thus, failure of the permeability barrier in itself favors secondary infection; and conversely, pathogen colonization/infection further aggravates the permeability barrier abnormality.…”

“…Increased colonization with S. aureus 66 occurs both as a result of the barrier abnormality (a structurally-competent, lipid-replete, acidic SC itself comprises a formidable barrier to pathogen colonization 11 , and it can further aggravate barrier function in AD by several mechanisms. The antimicrobial barrier is intimately linked to the permeability barrier 65 , and as with water egress, pathogen ingress occurs via the extracellular domains 67 . Moreover, an impaired permeability barrier alone predisposes to pathogen colonization, not only because of the increase in surface pH, but also because levels of FFA and the Cer metabolite, sphingosine, which exhibit potent in vitro antimicrobial activity 67,68 , decline in AD 11 .…”

“…Surface proteins on S. aureus can down-regulate epidermal FFA production, thereby aggravating both permeability and antimicrobial function in parallel, a strategy that could also facilitate microbial invasion. In addition, at least one member of epidermal AMP, the human cathelicidin product, LL-37, is down-regulated in a Th2-dependent fashion in AD 66,69 , and LL-37 is required for normal permeability barrier function 65 . Notably, LL-37 also displays robust activity against S. aureus, and is required not only for normal epidermal permeability barrier function, but also for the integrity of extracutaneous epithelia.…”

Innate Immune Defense System of the Skin

“…20 Synthesis of AMPs primarily occurs in the stratum granulosum; AMPs are then packaged into lamellar bodies and transported to the stratum corneum. 21 Sebocytes, mast cells and neutrophils are also important sources of AMPs in normal human skin. 20 Antimicrobial peptides are also present in skin secretions, such as saliva and sweat.…”

Basic structural and functional characteristics of the epidermal barrier in wild mammals living in different habitats and climates

“…The mammalian integument, in particular, mediates this broad spectrum of protective functions, whereby permeability and antimicrobial abilities are both co-regulated and interdependent, overlapping through the dual activities of their Communicated by C. Gortázar lipid/protein constituents (Elias 2007;Heung et al 2006;Aberg et al 2008).…”