CX3CR1 Deficiency Attenuates DNFB-Induced Contact Hypersensitivity Through Skewed Polarization Towards M2 Phenotype in Macrophages.

CX3CL1 can function as both an adhesion molecule and a chemokine for CX3CR1+ cells, such as T cells, monocytes, and NK cells. Recent studies have demonstrated that CX3CL1-CX3CR1 interaction is associated with the development of various inflammatory skin diseases. In this study, we examined CX3CR1 involvement in 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity using CX3CR1-/- mice. Ear swelling and dermal edema were attenuated after DNFB challenge in CX3CR1-/- mice. Expression of TNF-α, IL-6, and M1 macrophage markers was decreased in the ears of CX3CR1-/- mice, whereas expression of M2 macrophage markers including arginase-1 was increased. Decreased TNF-α and IL-6 expression and increased arginase-1 expression were found in peritoneal macrophages from CX3CR1-/- mice. Furthermore, ear swelling was attenuated by depleting dermal macrophages in wild-type mice to a similar level to CX3CR1-/- mice. These results suggest that CX3CR1 deficiency could induce skewed polarization towards M2 phenotype in macrophages, resulting in attenuation of contact hypersensitivity response.

Increased IL-26 Expression Promotes T Helper Type 17- and T Helper Type 2-Associated Cytokine Production by Keratinocytes in Atopic Dermatitis.

Whereas atopic dermatitis (AD) is considered as a T helper 2 (Th2)-centered disease, IL-17-producing Th (Th17) cells are also activated in AD lesional skin. However, the relationship between Th17 responses and Th2 responses in AD is still to be elucidated. Although Th17 cells are increased in AD skin, the expression and function of IL-26, which is also produced by Th17 cells, in AD are still unknown. In this report, we demonstrated that IL-26 mRNA expression levels were elevated in AD lesional skin compared with healthy controls and that IL-26-producing cells were increased in AD lesional skin by immunohistochemistry. Furthermore, IL-26 promoted IL-8, IL-1ß, chemokine (C-C motif) ligand 20, IL-33, and ß-defensin 2 production in keratinocytes through phosphorylation of signal transducer and activator of transcription 1 and signal transducer and activator of transcription 3. Selective JAK inhibitors for JAK1, JAK2, and tyrosine kinase 2 blocked IL-26-induced cytokine production in keratinocytes. We also showed that injection of IL-26 exacerbated an oxazolone-induced AD mouse model and upregulated Th2 and Th17 cytokine expression in vivo. Because previous studies indicate that the above molecules induced by IL-26 can promote Th17 and/or Th2 immune responses, IL-26 may play an important role for bridging between Th17 and Th2 responses, resulting in the development of AD.

Increased interleukin-36γ expression in skin and sera of patients with atopic dermatitis and mycosis fungoides/Sézary syndrome.

Interleukin (IL)-36γ is expressed by keratinocytes and functions as a key initiator of inflammation in the skin. IL-36γ expression is enhanced by tumor necrosis factor-α and IL-17A, having a strong association with psoriasis. In this study, we examined the role of IL-36γ in atopic dermatitis (AD) and mycosis fungoides (MF)/Sézary syndrome (SS). Serum levels of IL-36γ in AD patients and MF/SS patients were elevated compared with those of healthy controls. Importantly, serum IL-36γ levels in AD patients positively correlated with Eczema Area and Severity Index and those of MF/SS patients positively correlated with serum soluble IL-2 receptor levels. IL-36γ mRNA levels in AD skin and MF/SS skin were significantly higher than those of normal skin. IL-36γ mRNA levels in MF/SS skin positively correlated with IL-17A mRNA levels. Immunohistochemical staining revealed that IL-36γ was highly expressed in keratinocytes in lesional skin of AD and MF/SS. Taken together, our study demonstrated that IL-36γ expression was increased in sera and skin of patients with AD and MF/SS as was reported in psoriatic patients.

Increased endocan expression in lesional skin and decreased endocan expression in sera in atopic dermatitis.

Endocan is a novel human endothelial cell-specific molecule and is mainly expressed in endothelial cells in various tissues. Endocan has the capacity to inhibit leukocytes binding to the vascular endothelium. It also can promote the angiogenesis alongside vascular endothelial growth factor A. Through these functions, endocan has been implicated in the pathogenesis of various inflammatory diseases. To investigate the possible roles of endocan in atopic dermatitis (AD), we examined endocan expression in lesional skin and sera in patients with AD. Endocan mRNA and protein levels were increased in lesional skin of AD compared with healthy skin and endocan was expressed on epidermal keratinocytes and dermal endothelial cells. On the other hand, serum endocan levels in patients with AD were significantly lower than those in healthy controls. Our results suggest that elevated endocan expression in lesional skin may be associated with development of AD through angiogenesis and that decreased endocan expression in sera may be associated with increased leukocyte recruitment in AD.

Increased Interleukin-19 Expression in Cutaneous T-cell Lymphoma and Atopic Dermatitis.

Interleukin-19 (IL-19), a pro-inflammatory cytokine known to stimulate the production of T helper type 2 (Th2) cytokines, is induced by IL-17A and highly expressed in the lesional skin of psoriasis and atopic dermatitis (AD). This aim of this study was to investigate whether IL-19 is involved in cutaneous T-cell lym-phoma (CTCL) and AD. IL-19 levels were significantly higher in the sera of patients with AD and those with advanced-stage CTCL than in normal controls, correlating significantly with clinical disease markers. IL-19 mRNA levels in lesional skin of both diseases were significantly elevated. Immunohistochemical staining revealed that IL-19 was expressed in the epidermis of AD skin and CTCL skin. In vitro, IL-17A and IL-4 increased IL-19 mRNA expression in human keratinocytes. Thus, IL-19 was increased in the sera and skin of AD and CTCL. These results suggest that IL-19 is important for bridging Th17 to Th2 in these diseases.

Increased syndecan-4 expression in sera and skin of patients with atopic dermatitis.

Syndecan-4 (SDC-4) is a cell surface proteoglycan, which participates in signaling during cell adhesion, migration, proliferation, endocytosis, and mechanotransduction, and is expressed on various cells, including endothelial cells, epithelial cells, T cells, and eosinophils. Emerging evidences have suggested that SDC-4 might contribute to Th2-driven allergic immune responses. Here, we examined the role of SDC-4 in patients with atopic dermatitis (AD). Serum SDC-4 levels in AD patients were significantly higher than in healthy individuals, and they increased according to the disease severity. Importantly, they positively correlated with Eczema Area and Severity Index and itch visual analogue scale scores. Furthermore, serum SDC-4 levels decreased after treatment. We also analyzed SDC-4 expression in AD lesional skin. SDC-4 mRNA levels in AD skin were significantly higher than those of normal skin. Immunohistochemical staining revealed that SDC-4 was highly expressed in the epidermis and endothelial cells in AD lesional skin. Taken together, our study has demonstrated that SDC-4 expression was increased in sera and skin of AD patients, suggesting that SDC-4 may contribute to the development of AD.