title: Topical Treatment of Rosacea with Ivermectin Inhibits Gene Expression of Cathelicidin Innate Immune Mediators, LL-37 and KLK5, in Reconstructed and Ex Vivo Skin Models.
abstract: BACKGROUND
  Numerous intrinsic and extrinsic factors have been associated with the pathophysiology of rosacea, including dysregulation of innate immunity. A high level of cathelicidin antimicrobial peptides (e.g., LL-37) has been shown in the facial skin of patients with rosacea. Excessive production of both LL-37 and KLK5, the serine protease responsible for its cleavage, has been suggested to play a role in the pathophysiology of rosacea. Ivermectin 10 mg/g cream, indicated for the treatment of inflammatory lesions of rosacea, is reported to have dual anti-parasitic and anti-inflammatory properties. However, the exact mechanism of action of ivermectin cream in the treatment of rosacea is unknown.
  
  
  METHODS
  This study aimed to evaluate the effect of ivermectin on the expression of KLK5 and the subsequent effect on the maturation process of cathelicidins. Experimental studies were performed either on normal human epidermal keratinocytes (NHEK), reconstructed human epidermis (RHE) or on human skin ex vivo stimulated with calcitriol (1α,25-dihydroxyvitamin D3), which is known to induce KLK5 and LL-37 expression.
  
  
  RESULTS
  The results show that ivermectin is able to inhibit KLK5 and CAMP gene expression and protein secretion in NHEK cells stimulated with calcitriol. Those results were confirmed in 3D models of the skin (RHE and skin ex vivo). The anti-inflammatory effects of ivermectin were associated with an inhibition of IL-8, IL-6 and MCP-1 (CCL2) secretion from NHEK cells.
  
  
  CONCLUSIONS
  These results suggest that ivermectin can prevent the inflammatory effects of rosacea triggered by abnormal LL-37 processing, through the inhibition of KLK5 gene expression in the epidermis.
  
  
  BACKGROUND
  Nestlé Skin Health R&D.
authors.affiliation: Nestlé Skin Health R&D, Sophia Antipolis, France. Severine.THIBAUTDEMENONVILLE@galderma.com.
authors.forename: Séverine
authors.initials: S
authors.lastname: Thibaut de Ménonville
authors.affiliation: Nestlé Skin Health R&D, Sophia Antipolis, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Rosignoli
authors.affiliation: Nestlé Skin Health R&D, Sophia Antipolis, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Soares
authors.affiliation: Nestlé Skin Health R&D, Sophia Antipolis, France.
authors.forename: Manon
authors.initials: M
authors.lastname: Roquet
authors.affiliation: Nestlé Skin Health R&D, Sophia Antipolis, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Bertino
authors.affiliation: Nestlé Skin Health R&D, Sophia Antipolis, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Chappuis
authors.affiliation: Nestlé Skin Health R&D, Sophia Antipolis, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Defoin-Platel/Chaussade
authors.affiliation: Nestlé Skin Health R&D, Sophia Antipolis, France.
authors.forename: David
authors.initials: D
authors.lastname: Piwnica
keywords: Cathelicidin; Innate immunity; Ivermectin; Rosacea