Protecting the boundary: the sentinel role of host defense peptides in the skin

Abstract

The skin is our primary shield against microbial pathogens and has evolved innate and adaptive strategies to enhance immunity in response to injury or microbial insult. The study of antimicrobial peptide (AMP) production in mammalian skin has revealed several of the elegant strategies that AMPs use to prevent infection. AMPs are inducible by both infection and injury and protect the host by directly killing pathogens and/or acting as multifunctional effector molecules that trigger cellular responses to aid in the anti-infective and repair response. Depending on the specific AMP, these molecules can influence cytokine production, cell migration, cell proliferation, differentiation, angiogenesis and wound healing. Abnormal production of AMPs has been associated with the pathogenesis of several cutaneous diseases and plays a role in determining a patient’s susceptibility to pathogens. This review will discuss current research on the regulation and function of AMPs in the skin and in skin disorders.

Innate Immune Defense System of the Skin

“…12 Cutaneous AMPs are constitutively present and further induced by infection or injury or both (Figure 1). 4 In normal human skin, the main source of AMPs is the keratinocyte. 20 Synthesis of AMPs primarily occurs in the stratum granulosum; AMPs are then packaged into lamellar bodies and transported to the stratum corneum.…”

“…20 Antimicrobial peptides are also present in skin secretions, such as saliva and sweat. 4 Upon skin infection or injury or both, recruited neutrophils, mast cells and other leukocytes contribute to the majority of AMP production. 20 Production is triggered by activation of pattern recognition receptors, such as Toll-like receptors (TLRs), mannose receptors and helicases.…”

“…20 Production is triggered by activation of pattern recognition receptors, such as Toll-like receptors (TLRs), mannose receptors and helicases. 4 These receptors are activated by lipopolysaccharides from Gram-negative bacteria, lipoteichoic acid and peptidoglycans from Grampositive bacteria, mannans from yeast and fungi, and nucleic acids from pathogens and self. 4,22 Antimicrobial peptide upregulation is a secondary response, which limits the severity of infection or injury when the primary line of defense (constitutive AMP expression) fails.…”

“…4 These receptors are activated by lipopolysaccharides from Gram-negative bacteria, lipoteichoic acid and peptidoglycans from Grampositive bacteria, mannans from yeast and fungi, and nucleic acids from pathogens and self. 4,22 Antimicrobial peptide upregulation is a secondary response, which limits the severity of infection or injury when the primary line of defense (constitutive AMP expression) fails. 20 A major role of AMPs in innate immunity is their direct antibiotic-like inhibition of microbial pathogens.…”

“…The uppermost layer of the epidermis, the stratum corneum, consists of keratinocytes tightly linked by desmosomes in a hydrophobic cellular matrix, thereby creating an anatomical barrier against irritants, allergens and shear force. [4][5][6] In addition to an immediate physical barrier, this intrinsic resistance system functions through chemical mediators (cytokines), specialized signalling pathways, the complement cascade, leukocytes and host defense peptides [antimicrobial peptides (AMPs)]. In particular, AMP production is a critical mechanism for immune response of the skin to cutaneous infection and injury.…”