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

IntroductionNumerous 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.MethodsThis 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.ResultsThe 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.ConclusionsThese 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. Funding: Nestlé Skin Health R&D.Electronic supplementary materialThe online version of this article (doi:10.1007/s13555-017-0176-3) contains supplementary material, which is available to authorized users.

The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19: A pilot, double-blind, placebo-controlled, randomized clinical trial

“…Ivermectin is known to downregulate the expression of several pro-inflammatory genes, including those of IL-8, TNF-α, and cathelicidin LL-37 [29] . This effect is thought to partially explain the efficacy of ivermectin in the treatment of rosacea [ 29 , 30 ]. The effect on LL-37 might be particularly important, as this molecule directly influences several pro and anti-inflammatory pathways, including the stimulation of IL-18 and IL-1β production, and has a chemotactic effect for neutrophils and eosinophils [31] .…”

Inhibitory effect of timolol on topical glucocorticoid‑induced skin telangiectasia

“…Antibacterial peptides are expressed in mammals, birds and fish. They serve central roles in the natural immune response of the skin, which has been demonstrated in numerous animal and disease models, including those of rosacea, acne, atopic dermatitis, psoriasis and other inflammatory dermatoses ( 24 – 26 ). Antibacterial peptides may stimulate leukocyte chemotaxis, angiogenesis, and the expression of extracellular matrix components, which are involved in the clinical manifestations of erythema, papules and telangiectasia ( 26 ).…”

Antimicrobial Peptides and Their Therapeutic Potential for Bacterial Skin Infections and Wounds

“…Rosacea is accompanied by up-regulation of TLR2 which in turn triggers cathelicidin production leading to abnormally high levels in the epidermis and unusual cathelicidin cleaving products (Dutta and Das, 2015 ). A role of LL-37 in the pathogenesis of rosacea could be demonstrated by the application of ivermectin in keratinocytes and 3D skin models which displayed an anti-inflammatory effect by suppressing expression of LL-37 and the protease kallikrein-related peptidase (KLK)5 (Thibaut de Menonville et al, 2017 ).…”