Background Atopic dermatitis (AD) is a common disease, with an increasing prevalence. The primary pathogenesis of the disease is still elusive, resulting in the lack of specific treatments. AD is currently considered a biphasic disease, with Th2 predominating acute disease, and a switch to Th1 characterizing chronic disease. Elucidation of the molecular factors that participate in the onset of new lesions and maintenance of chronic disease is critical for the development of targeted therapeutics. Objectives We sought to characterize the mechanisms underlying onset and maintenance of AD. Methods We investigated intrapersonal sets of transcriptomes from non-lesional, acute and chronic lesions of ten AD patients through genomic, molecular and cellular profiling. Results Our study associated the onset of acute lesions with a striking increase in a subset of terminal differentiation proteins, specifically the cytokine-modulated S100A7, S100A8, and S100A9. Acute disease was also associated with significant increases in gene expression levels of major Th22- and Th2- cytokines, and smaller increases in IL-17. A lesser induction of Th1-associated genes was detected in acute disease, although some were significantly up-regulated in chronic disease. Further significant intensification of major Th22 and Th2 cytokines was observed between acute and chronic lesions. Conclusions Our data identified increased S100A7, S100A8 and S100A9 gene expression with AD initiation, and concomitant activation of Th2 and Th22 cytokines. Our findings support a model of progressive activation of Th2 and Th22 immune axes from acute to chronic phases, expanding the prevailing view of pathogenesis, with important therapeutic implications.

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Macrophages are important cells of the innate immune system, and their study is essential to gain greater understanding of the inflammatory nature of psoriasis. We used immunohistochemistry and double-label immunofluorescence to characterize CD163+ macrophages in psoriasis. Dermal macrophages were increased in psoriasis compared to normal skin and were identified by CD163, RFD7, CD68, LAMP2, Stabilin-1, and MARCO. CD163+ macrophages expressed C-lectins CD206/MMR and CD209/DC-SIGN, as well as co-stimulatory molecules CD86 and CD40. They did not express mature DC markers CD208/DC-LAMP, CD205/DEC205 or CD83. Microarray analysis of in vitro derived macrophages treated with IFNγ showed that many of the genes upregulated in macrophages were found in psoriasis, including STAT1, CXCL9, Mx1 and HLA-DR. CD163+ macrophages produced inflammatory molecules IL-23p19 and IL-12/23p40 as well as TNF and iNOS. These data demonstrate that CD163 is a superior marker of macrophages, and identifies a subpopulation of “classically activated” macrophages in psoriasis. We conclude that macrophages are likely to be contributing to the pathogenic inflammation in psoriasis, a prototypical Th1 and Th17 disease, by releasing key inflammatory products.

Background The molecular signature of atopic dermatitis/AD lesions is associated with Th2 and Th22 activation, and epidermal alterations. However, the epidermal and dermal AD transcriptomes and their respective contributions to abnormalities in respective immune and barrier phenotypes are unknown. Objective To establish the genomic profile of the epidermal and dermal compartments of lesional/LS and non-lesional/NL AD, as compared with normal skin. Methods Laser capture micro-dissection/LCM was performed to separate epidermis and dermis of LS and NL skin from AD patients and normal skin from healthy volunteers followed by gene expression (microarrays and RT-PCR) and immunostaining studies. Results Our study identified novel immune and barrier genes, including the IL-34 cytokine and claudins 4 and 8, and showed increased detection of key AD genes usually undetectable on arrays (i.e. IL-22, TSLP, CCL22, and CCL26). Overall, the combined epidermal and dermal transcriptomes enlarged the AD transcriptome adding 674 up-regulated and 405 down-regulated differentially expressed genes between LS and NL skin to the AD transcriptome. We were also able to localize individual transcripts as primarily epidermal (DEFB4A) or dermal (IL-22, CTLA4, and CCR7), and link their expressions to possible cellular sources. Conclusions This is the first report that establishes robust epidermal and dermal genomic signatures of LS, NL AD and normal/N skin, as compared with whole tissues. These data establish the utility of LCM to separate different compartments and cellular subsets in AD, allowing localization of key barrier or immune molecules, and enable detection of gene products usually not detected on arrays.

Inflammation-associated pigmentation changes are extremely common, but the etiology behind this clinical observation remains elusive. Particularly, it is unclear how the myriad of cytokines known to be involved in inflammatory skin processes affect epidermal melanocytes. We sought to determine how IL-17 and TNF influence normal human melanocytes, as these two cytokines have been implicated in various skin diseases. IL-17 and TNF jointly stimulated broad inductions of cytokines , including melanoma mitogens CXCL1 and IL-8. Moreover, IL-17 and TNF synergistically inhibited pigmentation-related signaling and melanin production, and induced keratinocytes production of β-defensin 3, an antagonist for melanocortin-receptor 1. When analyzing psoriasis lesions that are known to over express IL-17 and TNF, we observed an increase in melanocyte number and a simultaneous decrease in pigmentation signaling. Furthermore, therapeutic neutralization of TNF and IL-17 with mAbs results in a rapid recovery of pigment gene expression in psoriasis lesions. These results demonstrate that IL-17 and TNF can impact both the growth and pigment production of melanocytes, which may contribute to the pigmentation changes associated with psoriasis. These findings may allow the development of novel therapeutics for pigmentary disorders and bring new insights into the immune milieu surrounding melanocytes and related neoplasms.

BackgroundIL-17 is the defining cytokine of the Th17, Tc17, and γδ T cell populations that plays a critical role in mediating inflammation and autoimmunity. Psoriasis vulgaris is an inflammatory skin disease mediated by Th1 and Th17 cytokines with relevant contributions of IFN-γ, TNF-α, and IL-17. Despite the pivotal role IL-17 plays in psoriasis, and in contrast to the other key mediators involved in the psoriasis cytokine cascade that are capable of inducing broad effects on keratinocytes, IL-17 was demonstrated to regulate the expression of a limited number of genes in monolayer keratinocytes cultured in vitro.Methodology/Principal FindingsGiven the clinical efficacy of anti-IL-17 agents is associated with an impressive reduction in a large set of inflammatory genes, we sought a full-thickness skin model that more closely resemble in vivo epidermal architecture. Using a reconstructed human epidermis (RHE), IL-17 was able to upregulate 419 gene probes and downregulate 216 gene probes. As possible explanation for the increased gene induction in the RHE model is that C/CAAT-enhancer-binding proteins (C/EBP) -β, the transcription factor regulating IL-17-responsive genes, is expressed preferentially in differentiated keratinocytes.Conclusions/SignificanceThe genes identified in IL-17-treated RHE are likely relevant to the IL-17 effects in psoriasis, since ixekizumab (anti-IL-17A agent) strongly suppressed the “RHE” genes in psoriasis patients treated in vivo with this IL-17 antagonist.

Atopic dermatitis (AD) is a chronic or chronically-relapsing skin disorder characterized by the infiltration of T cells, eosinophils, mast cells and macrophages in lesional skin [1,2]. Enhanced serum IgE levels, specific IgE environmental allergens such as house dust mites, and blood eosinophilia are also present in the majority of AD patients. It has been proposed that Th2-type cells play a key role in the pathogenesis of AD because of the increased expression of Th2-related cytokines, such as IL-4 and IL-5, in lesional skin [3] and the high responsiveness of peripheral blood mononuclear cells to IL-4, but not IL-2 [4]. Previously, it was shown that serum soluble (s) E-selectin and serum sIL-2 receptor (R) significantly correlate with the disease activity of AD [5][6][7].Macrophage-derived chemokine (MDC), newly termed CCL22 [8], is a CC chemokine that potently serves as a chemoattractant for monocytes, monocyte-derived dendritic cells (DCs) and natural killer (NK) cells [9]. MDC is a ligand for CC chemokine receptor 4 (CCR4) [10], and is chemotactic for a fraction of CD4 + CD45RO + T cells polarized to produce Th2-type cytokines [11]. We have previously shown that in NC/Nga mice, a mouse model for human AD, dermal DCs are immunoreactive for MDC, and that the immunoreactivity of dermal DCs for MDC was abolished by topical corticosteroid treatment [12]. This indicates that the DC is a main source of MDC in lesional skin of AD. Very recently, we reported that levels of thymus and activationregulated chemokine (TARC), another ligand for CCR4, in AD sera significantly correlate with disease activity [13]. Moreover, it is reported that serum MDC levels in AD patients are higher than those in healthy controls [14], although the precise involvement of the high levels of MDC in AD has not yet been fully identified.We measured serum MDC levels in a large number of patients with AD, and compared them with levels in psoriasis vulgaris patients and healthy controls. We also examined the correlation between serum MDC levels, disease severity and the change in serum MDC levels in AD patients, before and after treatment. In addition, we compared serum MDC levels with laboratory data for AD disease markers such as serum soluble (s) SUMMARYAtopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease characterized by the predominant infiltration of T cells, eosinophils and macrophages in lesional skin. Recently, macrophagederived chemokine (MDC)/CCL22, a CC chemokine, was identified as a selective chemoattractant for CC chemokine receptor 4 (CCR4)-expressing cells, in addition to thymus and activation-regulated chemokine (TARC). We have previously reported that serum TARC levels correlate with the severity of AD. In this report, we investigated the participation of MDC in AD. First, we measured serum MDC levels in 45 patients with AD, 25 patients with psoriasis vulgaris and 25 healthy controls. Serum MDC levels in AD patients were significantly higher than those in healthy controls and psoriasis patients. Furt...

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