Makiko Kido-Nakahara

Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1–induced pruritus

In humans, pruritus (itch) is a common but poorly understood symptom in numerous skin and systemic diseases. Endothelin 1 (ET-1) evokes histamine-independent pruritus in mammals through activation of its cognate G protein-coupled receptor endothelin A receptor (ETAR). Here, we have identified neural endothelin-converting enzyme 1 (ECE-1) as a key regulator of ET-1-induced pruritus and neural signaling of itch. We show here that ETAR, ET-1, and ECE-1 are expressed and colocalize in murine dorsal root ganglia (DRG) neurons and human skin nerves. In murine DRG neurons, ET-1 induced internalization of ETAR within ECE-1-containing endosomes. ECE-1 inhibition slowed ETAR recycling yet prolonged ET-1-induced activation of ERK1/2, but not p38. In a murine itch model, ET-1-induced scratching behavior was substantially augmented by pharmacological ECE-1 inhibition and abrogated by treatment with an ERK1/2 inhibitor. Using iontophoresis, we demonstrated that ET-1 is a potent, partially histamine-independent pruritogen in humans. Immunohistochemical evaluation of skin from prurigo nodularis patients confirmed an upregulation of the ET-1/ETAR/ECE-1/ERK1/2 axis in patients with chronic itch. Together, our data identify the neural peptidase ECE-1 as a negative regulator of itch on sensory nerves by directly regulating ET-1-induced pruritus in humans and mice. Furthermore, these results implicate the ET-1/ECE-1/ERK1/2 pathway as a therapeutic target to treat pruritus in humans.

Atopic dermatitis: immune deviation, barrier dysfunction, IgE autoreactivity and new therapies

Atopic dermatitis (AD) is a chronic or chronically relapsing, eczematous, severely pruritic skin disorder mostly associated with IgE elevation and skin barrier dysfunction due to decreased filaggrin expression. The lesional skin of AD exhibits Th2- and Th22-deviated immune reactions that are progressive during disease chronicity. Th2 and Th22 cytokines further deteriorate the skin barrier by inhibiting filaggrin expression. Some IgEs are reactive to self-antigens. The IgE autoreactivity may precipitate the chronicity of AD. Upon activation of the ORAI1 calcium channel, atopic epidermis releases large amounts of thymic stromal lymphopoietin (TSLP), which initiates the Th2 and Th22 immune response. Th2-derived interleukin-31 and TSLP induce an itch sensation. Taken together, TSLP/Th2/Th22 pathway is a promising target for developing new therapeutics for AD. Enhancing filaggrin expression using ligands for the aryl hydrocarbon receptor may also be an adjunctive measure to restore the disrupted barrier function specifically for AD.

Antioxidant soybean tar Glyteer rescues T‐helper‐mediated downregulation of filaggrin expression via aryl hydrocarbon receptor

Soybean tar Glyteer (Gly) has been widely used for the treatment of various inflammatory skin diseases in Japan since 1924 as an alternative to coal tar remedy. Recently, coal tar has been shown to induce barrier repair in atopic dermatitis via aryl hydrocarbon receptor (AhR). In this study, we demonstrated that Gly activated AhR by inducing its cytoplasmic to nuclear translocation in keratinocytes. The AhR ligation by Gly was biologically active, with significant and dose‐dependent upregulation of CYP1A1 expression, which is a specific marker for AhR activation. Gly upregulated the expression of filaggrin in an AhR‐dependent manner because its enhancing effect was completely abrogated in AhR‐knockdown keratinocytes. T‐helper (Th)2 cytokines inhibited the expression of filaggrin; however, Gly completely restored the Th2‐mediated inhibition of filaggrin expression. Furthermore, Gly coordinately upregulated a series of epidermal differentiation complex genes, including involucrin, loricrin and hornerin. In addition, Gly exhibited potent antioxidant activity through the activation of nuclear factor‐erythroid 2‐related factor‐2 (Nrf2) and downstream antioxidant enzymes such as NAD(P)H:quinone oxidoreductase 1 (Nqo1), which actually inhibited the generation of reactive oxygen species in keratinocytes treated with tumor necrosis factor‐α or benzo[α]pyrene. In conclusion, antioxidant Gly rescues the downregulated expression of filaggrin (and plausibly other barrier proteins) in a Th2‐skewed milieu via AhR activation, which may partly explain its empirical anti‐inflammatory therapeutic effects.

Emerging role of interleukin-31 and interleukin-31 receptor in pruritus in atopic dermatitis

Atopic dermatitis (AD) is a chronic or chronically relapsing, eczematous, severely pruritic skin disorder associated with skin barrier dysfunction. The lesional skin of AD exhibits T helper 2 (TH2)‐deviated immune reactions. Interleukin‐31 (IL‐31), preferentially produced from TH2 cells, is a potent pruritogenic cytokine, and its systemic and local administration induces scratching behavior in rodents, dogs and monkeys. Recent clinical trials have revealed that administration of an anti‐IL‐31 receptor antibody significantly alleviates pruritus in patients with AD. In this review, we summarize recent topics related to IL‐31 and its receptor with special references to atopic itch.

Antioxidant Opuntia ficus-indica Extract Activates AHR-NRF2 Signaling and Upregulates Filaggrin and Loricrin Expression in Human Keratinocytes

UNLABELLED Opuntia ficus-indica (OFI) is a cactus species widely used as an anti-inflammatory, antilipidemic, and hypoglycemic agent. It has been shown that OFI extract (OFIE) inhibits oxidative stress in animal models of diabetes and hepatic disease; however, its antioxidant mechanism remains largely unknown. In this study, we demonstrated that OFIE exhibited potent antioxidant activity through the activation of nuclear factor erythroid 2-related factor 2 (NRF2) and the downstream antioxidant enzyme NAD(P)H quinone oxidoreductase 1 (NQO1), which inhibited the generation of reactive oxygen species in keratinocytes challenged with tumor necrosis factor α or benzo[α]pyrene. The antioxidant capacity of OFIE was canceled in NRF2 knockdown keratinocytes. OFIE exerted this NRF2-NQO1 upregulation through activation of the aryl hydrocarbon receptor (AHR). Moreover, the ligation of AHR by OFIE upregulated the expression of epidermal barrier proteins: filaggrin and loricrin. OFIE also prevented TH2 cytokine-mediated downregulation of filaggrin and loricrin expression in an AHR-dependent manner because it was canceled in AHR knockdown keratinocytes. Antioxidant OFIE is a potent activator of AHR-NRF2-NQO1 signaling and may be beneficial in treating barrier-disrupted skin disorders.

The transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction

Mutations of DOCK8 in humans cause a combined immunodeficiency characterized by atopic dermatitis with high serum IgE levels. However, the molecular link between DOCK8 deficiency and atopic skin inflammation is unknown. Here we show that CD4+ T cells from DOCK8-deficient mice produce large amounts of IL-31, a major pruritogen associated with atopic dermatitis. IL-31 induction critically depends on the transcription factor EPAS1, and its conditional deletion in CD4+ T cells abrogates skin disease development in DOCK8-deficient mice. Although EPAS1 is known to form a complex with aryl hydrocarbon receptor nuclear translocator (ARNT) and control hypoxic responses, EPAS1-mediated Il31 promoter activation is independent of ARNT, but in collaboration with SP1. On the other hand, we find that DOCK8 is an adaptor and negative regulator of nuclear translocation of EPAS1. Thus, EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction in CD4+ T cells.

Itch in Atopic Dermatitis

Chronic itch in inflammatory skin diseases, such as atopic dermatitis, markedly diminishes the quality of life of affected individuals. Comprehensive progress has been made in understanding itch signaling and associated mediators in the skin, dorsal root ganglia, spinal cord, and central nervous system, which may amplify or suppress atopic itch. Conventional therapies for atopic dermatitis are capable of reducing atopic itch; however, most patients are not satisfied with the antipruritic capacity of conventional treatments. Exploring itch pathways and mechanisms may lead to novel therapeutic approaches for atopic itch.

Pyoderma gangrenosum with increased levels of serum cytokines

A 66‐year‐old woman presented after an episode of accidental trauma with a painful ulcer on her scalp which rapidly enlarged in size, accompanied by central necrosis and undermining ulceration. The patients past history was negative for underlying systemic disease, although she had had a similar post‐traumatic intractable leg ulcer 3 years prior, which was unresponsive to surgical management but successfully treated with systemic steroids. A biopsied specimen from the scalp showed marked neutrophilic infiltrates in the dermis, compatible with a diagnosis of pyoderma gangrenosum (PG). The large ulcerative lesion responded very well to oral steroid therapy, showing rapid epithelialization. Serum levels of granulocyte colony‐stimulating factor and interleukin‐6 were significantly elevated prior to treatment, with decrease to normal levels after treatment. Serum tumor necrosis factor (TNF)‐α and granulocyte macrophage colony‐stimulating factor levels were within normal limits. The significance and pathogenic role of cytokine burst in PG is reviewed and discussed.

Generalized fixed drug eruption induced by tranexamic acid.

Tranexamic acid is a synthetic derivative of the amino acid that exerts an anti-plasmic effect. It is widely used to treat various diseases such as leukemia, hemophilia, prevention of blood loss in surgery or acute trauma, and hypermenorrhea. Besides its hemostatic effect, tranexamic acid is also applied in mucocutaneous diseases such as urticaria, angioedema, stomatitis and tonsillitis [1].Generally, tranexamic acid is well tolerated and considered to be relatively safe, provoking no serious adverse [...]

Changes in sebum levels and the development of acneiform rash in patients with non–small cell lung cancer after treatment with EGFR inhibitors

Background It has recently been shown that patients treated with epidermal growth factor receptor (EGFR) inhibitors often develop various cutaneous adverse events. While the pathogenesis underlying these events remains unclear, the relationship between skin toxicity induced by EGFR inhibitors and the sebaceous glands that express EGFR has been previously reported. Objectives The primary aim of this study was to determine the relationship between cutaneous sebum levels and acneiform rash, a typical skin toxicity of EGFR inhibitors, by measuring the sebum levels before and after EGFR inhibitor treatment. Methods Eight patients diagnosed with non–small cell lung cancer (NSCLC) (three men and five women with an average age of 69.3 years) who were initiated on treatment with EGFR inhibitors (either gefitinib [Iressa®] or erlotinib [Tarceva®]) were enrolled. Using a Sebumeter®, sebum levels in the face, chest, and back of each patient were measured before and after EGFR inhibitor treatment. The development of acneiform rash in each skin region was also assessed. Results Changes in sebum level along with the development of an acneiform rash were observed after patients were started on EGFR inhibitor treatment. Patients who developed an EGFR inhibitor–induced acneiform rash tended to have higher pretreatment sebum levels (baseline) than did patients who did not experience an acneiform rash. At each time point measurement, sebum levels were found to be significantly higher in patients who had developed an acneiform rash at that time. Patients who developed rash during treatment showed greater differences in sebum level compared with pretreatment baseline. Conclusion Patients who had increased levels of sebum or whose sebum levels showed greater change from pretreatment baseline developed an acneiform rash, suggesting that sebaceous gland activity may be involved in the mechanism underlying the development of acneiform rash, in patients treated with EGFR inhibitors.