Regulation of skin innate immunity by epidermal differentiation

通过表皮分化调节皮肤先天免疫

• 批准号: 15209035
• 负责人: HASHIMOTO Koji
• 金额: $ 31.45万
• 依托单位: Ehime University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15209035/
• 关键词: Epidermis; Keratinocyte; Differentiation; Innate Immunity; Toll-like receptor; Anti-microbial peptide; Wound Healing; Virus infection; 創傷治療; 皮膚; 表皮角化細胞; ASK1; toll-like receptor; MAP kinase; 細菌; MIP3α; 細胞内シグナル

Epidermal keratinocytes differentiate and form a multilayered epidermis, which is the primary barrier between the body and the outer environment. As the epidermis is constantly exposed to a variety of microbial pathogens, its function of resisting microbial pathogens is vital.Poly (I:C) treatment induced MIP-1? production in normal human keratinocytes. A neutralizing antibody for IFN-? significantly inhibited the poly (I:C)-induced MIP-1? production indicating that MIP-1??production is via IFN-?. IFN-? priming enhanced TLR3 expression and MIP-1? production in poly (I:C)-treated keratinocytes. This suggests that IFN-? enhanced the TLR3 expression and reinforced the response of keratinocytes to poly (I:C), which resulted in an increase in MIP-1??production. Therfore, normal human keratinocytes produce MIP-1? in response to dsRNA via TLR3, and this production is regulated by IFN-? ??.Immunohistochemical analysis revealed that the upper epidermis of normal human skin expresses ?-defensins (hBD) 1-3 and LL37. Transfection of ASK1-ΔN significantly enhanced the expression of hBD 1-3 and LL37 in normal human keratinocytes. In addition, a p38 inhibitor abolished this induction, indicating that ASK1-p38 regulates the expression of hBD1-3 and LL37. Furthermore, ASK1-p38 also regulated the expression of Toll-like receptor (TLR) 2 in keratinocytes. Therefore, ASK1-p38 regulates the innate immunity of the skin by forming an immune barrier consisting of hBDs, LL37, and TLR2 during epidermal differentiation.Skin wound closure is essential for resistance against microbial pathogens, and keratinocyte migration is an important step in skin wound healing. Since LL-37 is upregulated at skin wound sites, LL-37 may induce keratinocyte migration. In this study, we found that LL-37 induced keratinocyte migration via HB-EGF-mediated transactivation of EGFR. This study strongly suggests that LL-37 closes the skin wound by induction of keratinocyte migration.

表皮角质形成细胞分化形成多层表皮，是机体与外界环境之间的首要屏障，由于表皮不断暴露于多种微生物病原体，其抵抗微生物病原体的功能至关重要。 IFN-α 的中和抗体显着抑制了聚 (I:C) 诱导的 MIP-1? 的产生。 MIP-1β 的产生是通过 IFN-α 引发的，从而增强了经聚 (I:C) 处理的角质形成细胞中的 TLR3 表达和 MIP-1β 的产生。角质形成细胞转化为聚 (I:C)，从而导致 MIP-1α 产量增加。因此，正常人角质形成细胞通过 dsRNA 产生 MIP-1α。 TLR3，其产生受IFN-β调节。免疫组织化学分析显示，正常人皮肤上表皮表达β-防御素(hBD)1-3，转染ASK1-ΔN显着增强hBD1的表达。 -3 和 LL37 在正常人角质形成细胞中此外，p38 抑制剂消除了这种诱导，表明 ASK1-p38。此外，ASK1-p38 还调节角质形成细胞中 Toll 样受体 (TLR) 2 的表达，因此，ASK1-p38 通过形成免疫屏障来调节皮肤的先天免疫。表皮分化过程中的hBDs、LL37和TLR2。皮肤伤口闭合对于抵抗微生物病原体至关重要，而角质形成细胞迁移是重要的由于 LL-37 在皮肤伤口部位上调，因此 LL-37 可能会诱导角质形成细胞迁移。在这项研究中，我们发现 LL-37 通过 HB-EGF 介导的 EGFR 反式激活来诱导角质形成细胞迁移。强烈表明 LL-37 通过诱导角质形成细胞迁移来闭合皮肤伤口。

项目成果

Bone morphogenetic protein-2 modulates Wnt and frizzled expression and enhances the canonical pathway of Wnt signaling in normal keratinocytes.

• DOI: 10.1016/j.jdermsci.2005.12.011
• 发表时间: 2006-05
• 期刊: Journal of dermatological science
• 影响因子: 4.6
• 作者: Lujun Yang;K. Yamasaki;Y. Shirakata;X. Dai;S. Tokumaru;Y. Yahata;M. Tohyama;Y. Hanakawa;K. Sayama;K. Hashimoto

Urokinase-induced activation of the gp130/Tyk2/Stat3 pathway mediates a pro-inflammatory effect in human mesangial cells via expression of the anaphylatoxin C5a receptor

• DOI: 10.1242/jcs.03471
• 发表时间: 2007-06
• 期刊: Journal of Cell Science
• 影响因子: 4
• 作者: N. Shushakova;N. Tkachuk;M. Dangers;S. Tkachuk;Joon-Keun Park;K. Hashimoto;H. Haller;I. Dumler

Cre/loxP mediated gene transfer into living skin equivalent model

Cre/loxP 介导的基因转移到活体皮肤等效模型中

• 期刊: Br.J Dermatol (In press)
• 作者: Hanakawa Y;Shirakata Y;Sayama K;et al.
• 通讯作者: et al.

皮膚免疫ハンドブック改訂2版、自然免疫120-129p

皮肤免疫手册修订版第二版，先天免疫 120-129p。

• 发表时间: 2005
• 作者: Takai Y;Mitsuya M et al.;Memon IA;佐山浩二
• 通讯作者: 佐山浩二

Heparin-binding EGF-like growth factor accelerates keratinocyte migration and skin wound healing

• DOI: 10.1242/jcs.02346
• 发表时间: 2005-06-01
• 期刊: JOURNAL OF CELL SCIENCE
• 影响因子: 4
• 作者: Shirakata, Y;Kimura, R;Hashimoto, K
• 通讯作者: Hashimoto, K