Atopic dermatitis (AD) is characterized by chronic, eczematous, severe pruritic skin lesions caused by skin barrier dysfunction and T helper (Th)2 cell-mediated immunity.Interleukin (IL)-31 is a potent pruritogenic cytokine primarily produced by Th2 cells. [21] Human basophils serve as a source of IL-31 in the skin of chronic spontaneous urticaria patients.[17] | THE RECEP TOR OF IL-31The receptor for IL-31 consists of a heterodimer of IL-31 receptor α-chain (IL-31RA) and oncostatin M receptor β-chain (OSMR β).Intracellular signalling involving binding of the IL-31 receptor by IL-31 is mediated by the Janus kinase (JAK)-signal transducer and activator of transcription (STAT), phosphatidylinositol-3 kinase (PI3K)/ AKT (also known as protein kinase B or PKB) and mitogen-activated protein kinase (MAPK) pathways (Figure 1). [15,22] Phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) alone is insufficient to activate JAK1/JAK2 and STAT3. [23,24] Furthermore, it has been reported that missense mutations in the OSMR β gene were identified in the patients of familial primary localized cutaneous amyloidosis (FPLCA), hereditary skin disease associated with severe pruritus and deposition of amyloid material in the dermis. [25][26][27] OSMRβ | TARG E T CELL S AND EFFEC TS OF IL-31IL-31RA is expressed by immune cells such as activated macrophages, dendritic cells, eosinophils and basophils, as well as by epidermal keratinocytes and cutaneous peripheral nerves ( Figure 2). [12,17,19,28] | Immune cellsThe levels of IL-31RA expressed on human monocytes and macrophages are significantly elevated by Staphylococcal exotoxins. [29] Human dendritic cells significantly upregulate IL-31RA expression upon stimulation with interferon (IFN)-γ, and IL-31-stimulated dendritic cells release several pro-inflammatory cytokines such as tumor necrosis factor TNF)-α, IL-6, CXCL8, CCL2 CCL5 and CCL22. [30] IL-31RA expression by human mast cells is also upregulated by FcεRI aggregation. [31] Human basophils also express IL-31 receptors.IL-31 was shown to induce the secretion of IL-4 and IL-13 by basophils in vitro and to stimulate basophil chemotaxis.[17] IL-31-stimulated human eosinophils produced pro-inflammatory cytokines (IL-6and IL-1α) and chemokines (eg CXCL1, CCL2 and CCL5). Moreover, these phenomena were significantly upregulated in eosinophils cocultured with fibroblasts or keratinocytes in conjunction with IL-31 stimulation. [19,20] | Epidermal keratinocytesHuman epidermal keratinocytes abundantly express IL-31RA andOSMRβ. Epidermal keratinocytes of AD patients express high levels of IL-31RA compared with those of healthy subjects. IL-31 upregulates the expression levels of various chemokines, such as CCL17/TARC, CCL19/MIP-3β, CCL22/MDC, CCL23/MIP-3, CCL4/ MIP-1β and CXCL1/GRO1α in normal human epidermal keratinocytes (NHEKs). [1] In addition, IL-31 affects keratinocyte differentiation. IL-31 was shown to reduce the expression of epidermal keratinocyte differentiation-associated molecules such as filaggrin, c...

Atopic dermatitis (AD) is a common chronic skin inflammatory disorder characterized by recurrent eczema accompanied by an intractable itch that leads to an impaired quality of life. Extensive recent studies have shed light on the multifaceted pathogenesis of the disease. The complex interplay among skin barrier deficiency, immunological derangement, and pruritus contributes to the development, progression, and chronicity of the disease. Abnormalities in filaggrin, other stratum corneum constituents, and tight junctions induce and/or promote skin inflammation. This inflammation, in turn, can further deteriorate the barrier function by downregulating a myriad of essential barrier-maintaining molecules. Pruritus in AD, which may be due to hyperinnervation of the epidermis, increases pruritogens, and central sensitization compromises the skin integrity and promotes inflammation. There are unmet needs in the treatment of AD. Based on the detailed evidence available to date, certain disease mechanisms can be chosen as treatment targets. Numerous clinical trials of biological agents are currently being conducted and are expected to provide treatments for patients suffering from AD in the future. This review summarizes the etiopathogenesis of the disease and provides a rationale for choosing the novel targeted therapy that will be available in the future.

Hypoxia is a hallmark of cancer that is strongly associated with invasion, metastasis, resistance to therapy and poor clinical outcome. Tumour hypoxia affects immune responses and promotes the accumulation of macrophages in the tumour microenvironment. However, the signals linking tumour hypoxia to tumour-associated macrophage recruitment and tumour promotion are incompletely understood. Here we show that the damage-associated molecular pattern High-Mobility Group Box 1 protein (HMGB1) is released by melanoma tumour cells as a consequence of hypoxia and promotes M2-like tumour-associated macrophage accumulation and an IL-10 rich milieu within the tumour. Furthermore, we demonstrate that HMGB1 drives IL-10 production in M2-like macrophages by selectively signalling through the Receptor for Advanced Glycation End products (RAGE). Finally, we show that HMGB1 has an important role in murine B16 melanoma growth and metastasis, whereas in humans its serum concentration is significantly increased in metastatic melanoma. Collectively, our findings identify a mechanism by which hypoxia affects tumour growth and metastasis in melanoma and depict HMGB1 as a potential therapeutic target.

Eosinophils mediated the development of murine ICD, possibly through ROS production. Recruitment of eosinophils into the skin was induced by basophils in cooperation with fibroblasts. Our findings introduce the novel concept that basophils promote the recruitment of eosinophils into the skin through fibroblasts in the development of skin inflammation.

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