Antimicrobial peptides and the skin immune defense system

Abstract

Our skin is constantly challenged by microbes but is rarely infected. Cutaneous production of antimicrobial peptides (AMPs) is a primary system for protection, and expression of some AMPs further increases in response to microbial invasion. Cathelicidins are unique AMPs that protect the skin through 2 distinct pathways: (1) direct antimicrobial activity and (2) initiation of a host response resulting in cytokine release, inflammation, angiogenesis, and reepithelialization. Cathelicidin dysfunction emerges as a central factor in the pathogenesis of several cutaneous diseases, including atopic dermatitis, in which cathelicidin is suppressed; rosacea, in which cathelicidin peptides are abnormally processed to forms that induce inflammation; and psoriasis, in which cathelicidin peptide converts self-DNA to a potent stimulus in an autoinflammatory cascade. Recent work identified vitamin D3 as a major factor involved in the regulation of cathelicidin. Therapies targeting control of cathelicidin and other AMPs might provide new approaches in the management of infectious and inflammatory skin diseases.

FIG 1

Models for cell activation by cathelicidins. Multiple mechanisms have been proposed for cathelicidins to stimulate a cellular response. Responses are dependent on activation of G protein–coupled receptors and transactivation of the epidermal growth factor receptor or secondary to intracellular Ca²⁺ mobilization or a change in cell membrane function, leading to alterations in receptor responses. Finally, cathelicidins can influence the function of TLRs through both direct and indirect pathways. EGF-R, Epidermal growth factor receptor; IP-10, IFN-γ–inducible protein 10; MCP-1, monocyte chemoattractant protein 1; MIP3α, macrophage inflammatory protein 3α; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; STAT, signal transducer and activator of transcription.

FIG 2

Mechanisms of vitamin D3 activation and cathelicidin response. Extrarenal metabolism of vitamin D3 by keratinocytes provides a system for rapid control of cathelicidin expression. Activation of 25D3 to 1,25D3 requires 2 hydroxylation steps that occur sequentially in the liver and kidney. However, keratinocytes also express CYP27B1, a 1α-hydroxylase that activates 1,25D3. CYP27B1 expression in keratinocytes is controlled by danger signals during skin infection and tissue damage.