記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Investigative Dermatology  

DOI： 10.1016/j.jid.2023.10.002

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Molecular Sciences  

Interleukin (IL)-33 and IL-37 have been identified as novel cytokines involved in various inflammatory diseases. However, their specific roles remain largely unknown. Recent studies have shown that IL-33, which triggers inflammation, and IL-37, which suppresses it, cooperatively regulate the balance between inflammation and anti-inflammation. IL-33 and IL-37 are also deeply involved in the pathogenesis of inflammatory skin diseases such as atopic dermatitis (AD) and psoriasis. Furthermore, a signaling pathway by which aryl hydrocarbon receptor (AHR), a receptor for dioxins, regulates the expression of IL-33 and IL-37 has been revealed. Here, we outline recent findings on the mechanisms regulating IL-33 and IL-37 expression in AD and psoriasis. IL-33 expression is partially dependent on mitogen-activated protein kinase (MAPK) activation, and IL-37 has a role in suppressing MAPK in human keratinocytes. Furthermore, IL-33 downregulates skin barrier function proteins including filaggrin and loricrin, thereby downregulating the expression of IL-37, which colocalizes with these proteins. This leads to an imbalance of the IL-33–IL-37 axis, involving increased IL-33 and decreased IL-37, which may be associated with the pathogenesis of AD and psoriasis. Therefore, AHR-mediated regulation of the IL-33–IL-37 axis may lead to new therapeutic strategies for the treatment of AD and psoriasis.

DOI： 10.3390/ijms241914633

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Investigative Dermatology  

DOI： 10.1016/j.jid.2022.12.026

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Investigative Dermatology  

LL37 is produced by skin injury and bacterial infection and plays an important role in the early stages of psoriasis. In particular, the intracellular receptors toll-like receptors (TLR)3, TLR7, TLR8, and TLR9 are thought to be involved in the pathogenesis of psoriasis in conjunction with LL37, but the interaction between TLR7/8 and LL37 in keratinocytes (KCs) remains unclear. This study aimed to clarify the relationship between LL37 and TLR7/8 in KCs and their involvement in the pathogenetic pathways seen in psoriasis using cultured KCs and skin samples of patients with psoriasis. TLR7/8 was induced by LL37 in KCs. TLR8 but not TLR7 functionally induced many psoriasis-related molecules, whereas IL-17C was not altered by the blockade of TLR7/8. Although costimulation of LL37 with self-RNA/DNA did not show any interaction, LL37 itself would promote psoriasis-related genes. IL-36 receptor antagonistic antibody suppressed IL-17C induced by LL37. In psoriatic epidermis, LL37, TLRs, IL-17C, and IL-36γ expressions were increased and coexpressed with each other. Thus, we concluded that LL37 activates TLR8 in KCs and induces IL-17C through the induction of IL-36γ. Regulation of TLR8 or LL37 in KCs could be a potential therapeutic strategy for psoriatic inflammation.

DOI： 10.1016/j.jid.2022.10.017

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatological Science  

BACKGROUND: Difamilast, a topical phosphodiesterase 4 (PDE4) inhibitor, has been shown to be effective for treating atopic dermatitis (AD), but the molecular mechanism involved is unclear. Since skin barrier dysfunction including reduced expression of filaggrin (FLG) and loricrin (LOR) contributes to AD development, difamilast treatment may be able to improve this dysfunction. PDE4 inhibition increases transcriptional activity of cAMP-responsive element binding protein (CREB). Therefore, we hypothesized that difamilast may affect FLG and LOR expression via CREB in human keratinocytes. OBJECTIVE: To elucidate the mechanism by which difamilast regulates FLG and LOR expression via CREB in human keratinocytes. METHODS: We analyzed normal human epidermal keratinocytes (NHEKs) treated with difamilast. RESULTS: We observed increases of intracellular cAMP levels and CREB phosphorylation in difamilast (5 μM)-treated NHEKs. Next, we found that difamilast treatment increased mRNA and protein levels of FLG and LOR in NHEKs. Since reduced expression of keratinocyte proline-rich protein (KPRP) is reported to be involved in skin barrier dysfunction in AD, we examined KPRP expression in difamilast-treated NHEKs. We found that difamilast treatment increased mRNA and protein levels of KPRP in NHEKs. Furthermore, KPRP knockdown using siRNA transfection abolished the upregulation of FLG and LOR in difamilast-treated NHEKs. Finally, CREB knockdown canceled the upregulation of FLG, LOR, and KPRP in difamilast-treated NHEKs, indicating that PDE4 inhibition by difamilast treatment positively regulates FLG and LOR expression via the CREB-KPRP axis in NHEKs. CONCLUSION: These findings may provide further guidance for therapeutic strategies in the treatment of AD using difamilast.

DOI： 10.1016/j.jdermsci.2023.04.007

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記述言語：英語   出版者・発行元：エルゼビア・ジャパン(株)  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Biomedicines  

Atopic dermatitis (AD) is a chronic inflammatory skin disease that significantly impacts quality of life. The pathogenesis of AD is a complex combination of skin barrier dysfunction, type II immune response, and pruritus. Progress in the understanding of the immunological mechanisms of AD has led to the recognition of multiple novel therapeutic targets. For systemic therapy, new biologic agents that target IL-13, IL-22, IL-33, the IL-23/IL-17 axis, and OX40-OX40L are being developed. Binding of type II cytokines to their receptors activates Janus kinase (JAK) and its downstream signal, namely signal transduction and activator of transcription (STAT). JAK inhibitors block the activation of the JAK-STAT pathway, thereby blocking the signaling pathways mediated by type II cytokines. In addition to oral JAK inhibitors, histamine H4 receptor antagonists are under investigation as small-molecule compounds. For topical therapy, JAK inhibitors, aryl hydrocarbon receptor modulators, and phosphodiesterase-4 inhibitors are being approved. Microbiome modulation is also being examined for the treatment of AD. This review outlines current and future directions for novel therapies of AD that are currently being investigated in clinical trials, focusing on their mechanisms of action and efficacy. This supports the accumulation of data on advanced treatments for AD in the new era of precision medicine.

DOI： 10.3390/biomedicines11051303

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記述言語：英語   出版者・発行元：Allergy: European Journal of Allergy and Clinical Immunology  

DOI： 10.1111/all.15429

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Clinical Medicine  

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases, and the condition is typified by barrier dysfunction and immune dysregulation. Recent studies have characterized various phenotypes and endotypes of AD and elucidated the mechanism. Numerous topical and systemic narrow targeting therapies for AD have been developed according to these findings. Topical medications, including Janus kinase (JAK) inhibitors, phosphodiesterase 4 inhibitors, and the aryl hydrocarbon receptor agonist tapinarof, are effective and safe for AD compared to topical corticosteroids. Oral JAK inhibitors and monoclonal antibodies targeting interleukin (IL)-4, IL-13, IL-31, IL-33, OX40, thymic stromal lymphopoietin, and sphingosine 1-phosphate signaling have displayed outstanding efficacy against moderate-to-severe AD. We are currently in a new era of AD treatment.

DOI： 10.3390/jcm11206145

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記述言語：英語  

DOI： 10.1111/1346-8138.16422

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記述言語：英語  

DOI： 10.1111/all.15035

記述言語：英語  

DOI： 10.1016/j.jid.2021.01.019

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/jcm9030618

記述言語：英語  

DOI： 10.1016/j.jaci.2019.06.031

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jdermsci.2019.07.005

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jdermsci.2019.04.002

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jdermsci.2018.04.010

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1126/scisignal.aao4874

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2340/00015555-2808

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/ncomms13946

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/1346-8138.13360

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2340/00015555-1989

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/1346-8138.12578

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Mast cells play a key role in the induction of anaphylaxis, a life-threatening IgE-dependent allergic reaction, by secreting chemical mediators that are stored in secretory granules. Degranulation of mast cells is triggered by aggregation of the high-affinity IgE receptor, FcεRI, and involves dynamic rearrangement of microtubules. Although much is known about proximal signals downstream of FcεRI, the distal signaling events controlling microtubule dynamics remain elusive. Here we report that DOCK5, an atypical guanine nucleotide exchange factor (GEF) for Rac, is essential for mast cell degranulation. As such, we found that DOCK5-deficient mice exhibit resistance to systemic and cutaneous anaphylaxis. The Rac GEF activity of DOCK5 is surprisingly not required for mast cell degranulation. Instead, DOCK5 associated with Nck2 and Akt to regulate microtubule dynamics through phosphorylation and inactivation of GSK3β. When DOCK5-Nck2-Akt interactions were disrupted, microtubule formation and degranulation response were severely impaired. Our results thus identify DOCK5 as a key signaling adaptor that orchestrates remodeling of the microtubule network essential for mast cell degranulation.

DOI： 10.1084/jem.20131926

記述言語：英語  

DOI： 10.1016/j.jdermsci.2013.05.008

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1346-8138.2010.01177.x