Keratinocyte Production of Cathelicidin Provides Direct Activity against Bacterial Skin Pathogens

Abstract

Immune defense at an interface with the external environment reflects the functions of physical and chemical barriers provided by epithelial and immune cells. Resident epithelial cells, such as keratinocytes, produce numerous peptides with direct antimicrobial activity but also provide a physical barrier against invading pathogens and signal the recruitment of circulating immune cells, such as neutrophils. Antimicrobial peptides such as cathelicidin are produced constitutively by neutrophils and are inducible in keratinocytes in response to infection. The multiplicity of antimicrobial peptides and their cellular sources has resulted in an incomplete understanding of the role of cathelicidin production by epithelial cells in cutaneous immune defense. Therefore, this study sought to evaluate keratinocyte antimicrobial activity and the potential contribution of keratinocyte cathelicidin to host protection against two leading human skin pathogens. Wild-type mice and those with a targeted deletion of the cathelicidin gene, Cnlp, were rendered neutropenic prior to cutaneous infection. Interestingly, Cnlp-deficient mice remained more susceptible to group A streptococcus infection than mice with Cnlp intact, suggesting the involvement of epithelial cell-derived cathelicidin in host immune defense. Keratinocytes were then isolated in culture and found to inhibit the growth of Staphylococcus aureus, an effect that was partially dependent on their ability to synthesize and activate cathelicidin. Further, lentivirusmediated delivery of activated human cathelicidin enhanced keratinocyte antimicrobial activity. Combined, these data illustrate the potential contribution of keratinocyte cathelicidin to the innate immune defense of skin against bacterial pathogens and highlight the need to consider epithelial antimicrobial function in the diagnosis and therapy of skin infection.

Ctriporin, a New Anti-Methicillin-Resistant Staphylococcus aureus Peptide from the Venom of the Scorpion Chaerilus tricostatus

“…Many cell types that permanently reside in skin produce AMPs, including keratinocytes, sebocytes, eccrine glands, and mast cells on May 12, 2018 by guest http://aac.asm.org/ (7,31). AMPs are important for skin health; decreased expression of AMPs may result in some skin diseases such as atopic dermatitis (37), as well as skin injury and infection (10,38).…”

Host Defense Peptides in Wound Healing

“…Expression decreased after wound closure, and a lack of LL-37 in chronic wounds was reported (143). Different authors have shown a protective function of LL-37 from invasive bacterial skin infections, particularly against P. aeruginosa, S. aureus, and group A Streptococcus (36,101,144,145). Comparing wildtype mice with Cnlp-deficient mice (targeted deletion of the cathelicidin gene), a prolonged period of wound healing and an increase in bacterial colonization for Cnlp-deficient mice was reported (145).…”

“…Different authors have shown a protective function of LL-37 from invasive bacterial skin infections, particularly against P. aeruginosa, S. aureus, and group A Streptococcus (36,101,144,145). Comparing wildtype mice with Cnlp-deficient mice (targeted deletion of the cathelicidin gene), a prolonged period of wound healing and an increase in bacterial colonization for Cnlp-deficient mice was reported (145). These findings were confirmed by Nizet et al (144), who reported a better outcome for wild-type mice versus Cnlp-deficient mice after challenge with necrotic skin infections of Group A Streptococcus.…”

Current Drug Therapies for Rosacea: A Chronic Vascular and Inflammatory Skin Disease

“…[23][24][25] Some forms of these cathelicidin peptides have vasoactive and proinflammatory activities leading to modification of dermal structures through vascular changes and collagen degeneration. 26,27 Cathelicidins are processed by an epidermal serine protease called kallikrein 5 (KLK5). 28 Patients with rosacea have elevated expression and elevated protease activity of KLK5.…”