Acne rosacea is an inflammatory skin disease that affects 3% of the US population over 30 years of age and is characterized by erythema, papulopustules and telangiectasia. The etiology of this disorder is unknown, although symptoms are exacerbated by factors that trigger innate immune responses, such as the release of cathelicidin antimicrobial peptides. Here we show that individuals with rosacea express abnormally high levels of cathelicidin in their facial skin and that the proteolytically processed forms of cathelicidin peptides found in rosacea are different from those present in normal individuals. These cathelicidin peptides are a result of a post-translational processing abnormality associated with an increase in stratum corneum tryptic enzyme (SCTE) in the epidermis. In mice, injection of the cathelicidin peptides found in rosacea, addition of SCTE, and increasing protease activity by targeted deletion of the serine protease inhibitor gene Spink5 each increases inflammation in mouse skin. The role of cathelicidin in enabling SCTE-mediated inflammation is verified in mice with a targeted deletion of Camp, the gene encoding cathelicidin. These findings confirm the role of cathelicidin in skin inflammatory responses and suggest an explanation for the pathogenesis of rosacea by demonstrating that an exacerbated innate immune response can reproduce elements of this disease.

The production of antimicrobial peptides and proteins is essential for defense against infection. Many of the known human antimicrobial peptides are multifunctional, with stimulatory activities such as chemotaxis while simultaneously acting as natural antibiotics. In humans, eccrine appendages express DCD and CAMP, genes encoding proteins processed into the antimicrobial peptides dermcidin and LL-37. In this study we show that after secretion onto the skin surface, the CAMP gene product is processed by a serine protease-dependent mechanism into multiple novel antimicrobial peptides distinct from the cathelicidin LL-37. These peptides show enhanced antimicrobial action, acquiring the ability to kill skin pathogens such as Staphylococcus aureus and Candida albicans. Furthermore, although LL-37 may influence the host inflammatory response by stimulating IL-8 release from keratinocytes, this activity is lost in subsequently processed peptides. Thus, a single gene product encoding an important defense molecule alters structure and function in the topical environment to shift the balance of activity toward direct inhibition of microbial colonization.

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The eccrine gland is one of the major cutaneous appendages and secretes sweat. Its principal function is thermoregulation during exposure to a hot environment or physical exercise. In addition to this function, we show that LL-37, a member of cathelicidin family of anti-microbial peptides, is expressed in sweat. LL-37 protein and mRNA was seen in the eccrine structures of normal human skin by immunohistochemistry and in situ hybridization. LL-37 was localized to both the eccrine gland and sweat ductal epithelial cells, whereas dermcidin, a previously described natural antibiotic in sweat, was expressed only in the gland itself. The anti-microbial activity of LL-37 and dermcidin against various bacteria in the sweat ionic environment was demonstrated by solution colony forming assay using synthetic peptides, and in sweat obtained from normal volunteers. These results indicate that cathelicidin is secreted in human sweat, has potent anti-microbial activity against both gram-positive and gram-negative bacteria, and can, after processing from the preproform, provide a barrier for protection against infection. Thus, sweat represents a unique mode of delivery for potent innate immune effector molecules in the absence of inflammation.

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Here we show that keratinocytes in psoriatic lesional skin express increased Toll-like receptor (TLR) 9 that similarly localizes with elevated expression of the cathelicidin antimicrobial peptide LL-37. In culture, normal human keratinocytes exposed to LL-37 increased TLR9 expression. Furthermore, when keratinocytes were exposed to LL-37 and subsequently treated with TLR9 ligands such as CpG or genomic DNA, keratinocytes greatly increased production of type I interferons. This response mimicked observations in the epidermis of psoriatic lesional skin as keratinocytes in psoriatic lesions produce greater amounts of interferon-β than normal skin lacking LL-37. The mechanism for induction of type I interferons in keratinocytes was dependent on TLR9 expression but not on a DNA-LL-37 complex. These findings suggest that keratinocytes recognize and respond to DNA and can actively participate in contributing to the immunological environment that characterizes psoriasis.

The expression of antimicrobial peptides at epithelial surfaces such as skin, lung, and intestine is thought to provide protection against infection. Cathelicidin antimicrobial peptides are essential for the protection of skin against invasive bacterial infection. To determine if cathelicidins are also present in the oral cavity, we examined the expression of both mRNA and protein in mice and human saliva. The murine cathelicidin (CRAMP) was detected in the adult by reverse-transcription/polymerase chain-reaction (RT-PCR), and in embryonic, newborn, and adult tissues by in situ hybridization and immunohistochemistry. CRAMP mRNA and protein were localized to the salivary glands, specifically in acinar cells of the submandibular gland and palatine minor glands, as well as in lingual epithelium and palatal mucosa. In man, the human cathelicidin LL-37 was detected in human saliva by Western blotting. These results indicate that cathelicidins are present in the salivary system, in some oral epithelia, and in saliva, contributing to broad-spectrum defense of the oral cavity.

Background: Psoriasis severity categories have been important tools for clinicians to use in treatment decisions as well as to determine eligibility criteria for clinical studies. However, owing to the heterogeneity of severity classifications and their lack of consideration for the impact of psoriasis involvement of special areas or past treatment history, patients may be miscategorized, which can lead to undertreatment of psoriasis.Objective: To develop a consensus statement on the classification of psoriasis severity.Methods: A modified Delphi approach was developed by the International Psoriasis Council to define psoriasis severity.Results: After completion of the exercise, 7 severity definitions were preferentially ranked. This most preferred statement rejects the mild, moderate, and severe categories in favor of a dichotomous definition: Psoriasis patients should be classified as either candidates for topical therapy or candidates for systemic