Rosacea as a Disease of Cathelicidins and Skin Innate Immunity

Department of Dermatology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan.
Journal of Investigative Dermatology Symposium Proceedings (Impact Factor: 3.73). 12/2011; 15(1):12-5. DOI: 10.1038/jidsymp.2011.4
Source: PubMed


Rosacea is a common and chronic inflammatory skin disease most frequently seen in groups of genetically related individuals. Although the symptoms of rosacea are heterogeneous, they are all related by the presence of characteristic facial or ocular inflammation involving both the vascular and tissue stroma. Until recently, the pathophysiology of this disease was limited to descriptions of a wide variety of factors that exacerbate or improve disease. Recent molecular studies show a common link between the triggers of rosacea and the cellular response, and these observations suggest that an altered innate immune response is involved in disease pathogenesis. Understanding rosacea as a disorder of innate immunity explains the benefits of current treatments and suggests new therapeutic strategies for alleviating this disease.

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    • "Th1/Th17 Immune Response in Rosacea elevated and abnormally processed (Yamasaki et al., 2007), and pattern-recognition receptors (TLR2, NALP3) were upregulated (Yamasaki et al., 2011; Casas et al., 2012). As the kallikrein (KLK) serine proteases 5 and 7 are major activators of antimicrobial peptides such as cathelicidin, the abundance of KLK5 in rosacea is responsible for processing the excess cathelicidins into aberrant forms, which fuels the course of the disease (Yamasaki et al., 2007). "
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    ABSTRACT: Rosacea is a common chronic inflammatory skin disease of unknown etiology. Our knowledge about an involvement of the adaptive immune system is very limited. We performed detailed transcriptome analysis, qRT-PCR, and quantitative immunohistochemistry on facial biopsies of rosacea patients, classified according to their clinical subtype. As controls, we used samples from patients with facial lupus erythematosus and healthy controls. Our study shows significant activation of the immune system in all subtypes of rosacea, characterizing erythematotelangiectatic rosacea (ETR) already as a disease with significant influx of proinflammatory cells. The T cell response is dominated by Th1/Th17-polarized immune cells, as demonstrated by significant upregulation of IFNγ or IL-17, for example. Chemokine expression patterns support a Th1/Th17 polarization profile of the T cell response. Macrophages and mast cells are increased in all three subtypes of rosacea, while neutrophils reach a maximum in papulopustular rosacea. Our studies also provide evidence for activation of plasma cells with significant antibody production already in ETR, followed by a crescendo pattern towards phymatous rosacea. In sum, Th1/Th17 polarized inflammation and macrophage infiltration is an underestimated hallmark in all subtypes of rosacea. Therapies directly targeting the Th1/Th17 pathway are promising candidates in the future treatment of this skin disease.Journal of Investigative Dermatology accepted article preview online, 07 April 2015. doi:10.1038/jid.2015.141.
    Journal of Investigative Dermatology 04/2015; 135(9). DOI:10.1038/jid.2015.141 · 7.22 Impact Factor
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    • "Despite a structural diversity among species, all cathelicidins display typical physico-chemical features of AMPs; and LL-37 plays diverse interconnected biological roles in the physiology of human tissues (Bals and Wilson 2003; Tomasinsig and Zanetti 2005; Wong et al. 2013). Recent research has shown that cathelicidins and their complexes with DNA or other biomolecules are implicated in the development or exacerbation of severe skin diseases such as systemic lupus erythematosus and psoriasis, as well as the inflammatory damage of tissue in arthritis (Morizane and Gallo 2012; Yamasaki and Gallo 2011; Hoffmann et al. 2013). "
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    ABSTRACT: Cathelicidins are phylogenetically ancient, pleiotropic host defense peptides—also called antimicrobial peptides (AMPs)—expressed in numerous life forms for innate immunity. Since even the jawless hagfish expresses cathelicidins, these genetically encoded host defense peptides are at least 400 million years old. More recently, cathelicidins with varying antipathogenic activities and cytotoxicities were discovered in the venoms of poisonous snakes; for these creatures, cathelicidins may also serve as weapons against prey and predators, as well as for innate immunity. We report herein the expression of orthologous cathelicidin genes in the venoms of four different South American pit vipers (Bothrops atrox, Bothrops lutzi, Crotalus durissus terrificus, and Lachesis muta rhombeata)—distant relatives of Asian cobras and kraits, previously shown to express cathelicidins—and an elapid, Pseudonaja textilis. We identified six novel, genetically encoded peptides: four from pit vipers, collectively named vipericidins, and two from the elapid. These new venom-derived cathelicidins exhibited potent killing activity against a number of bacterial strains (S. pyogenes, A. baumannii, E. faecalis, S. aureus, E. coli, K. pneumoniae, and P. aeruginosa), mostly with relatively less potent hemolysis, indicating their possible usefulness as lead structures for the development of new anti-infective agents. It is worth noting that these South American snake venom peptides are comparable in cytotoxicity (e.g., hemolysis) to human cathelicidin LL-37, and much lower than other membrane-active peptides such as mastoparan 7 and melittin from bee venom. Overall, the excellent bactericidal profile of vipericidins suggests they are a promising template for the development of broad-spectrum peptide antibiotics.
    Amino Acids 08/2014; 46(11). DOI:10.1007/s00726-014-1801-4 · 3.29 Impact Factor
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    • "Proposed mechanism of anatabine's effects on the proinflammatory signaling pathways involved in rosacea. The key molecular components believed to be involved in the proinflammatory signaling pathways and pathophysiology of rosacea are shown [4, 5, 6, 7, 15]. The proposed mechanism of anatabine's effects on rosacea signs and symptoms is through interference with the activation and translocation of transcription factors such as NF-κB and STAT3 involved in the propagation of proinflammatory signaling pathways. "
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    ABSTRACT: Current medical and scientific research indicates that rosacea, a chronic and often debilitating skin condition that primarily affects the central face, may be caused by an overactive or excessive inflammatory immune response. Regardless of etiology, the accompanying redness and inflammation is unsightly and difficult for the patient. Anatabine is an alkaloid from the plant family Solanaceae that has been shown in several preclinical studies to modulate proinflammatory signaling pathways. A cream containing anatabine was developed and evaluated in an open-label case series study for safety and effects on the appearance of the skin in 10 patients with mild to moderate rosacea. Patients applied the cream to the face twice daily for a period of 30 days. Patients and the study physician completed safety and efficacy assessments at study end. Results showed that 50% of the patients self-reported improvement in the appearance of their skin, and the physician noted improvement in 70% of the patients. Photographs taken before and after 30 days of cream use provide visual evidence of the improvement in several patients. There were no complications or adverse events reported by any of the patients in the study, indicating that the anatabine cream was safe and very well tolerated. The results of this open-label case series show that a facial cream containing anatabine can improve the appearance of the skin in patients with mild to moderate rosacea and suggest that a double-blind, vehicle-controlled trial in a larger number of subjects is warranted.
    Case Reports in Dermatology 11/2013; 5(3):347-356. DOI:10.1159/000357019
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