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并形成多层表皮，其是身体与外部环境之间的主要屏障。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。Poly（I：C）处理诱导了MIP-1？在正常人角质形成细胞中产生。干扰素中和抗体？显著抑制poly（I：C）诱导的MIP-1？生产表明，MIP-1？？生产是通过IFN-？。IFN-？引发增强TLR3表达和MIP-1？在poly（I：C）处理的角质形成细胞中产生。这表明IFN-？增加TLR3的表达，增强角质形成细胞对poly（I：C）的反应，从而导致MIP-1？生产因此，正常人角质形成细胞产生MIP-1？响应dsRNA通过TLR3，这种生产是由IFN-？??.免疫组织化学分析显示，正常人皮肤的上表皮表达？防御素（hBD）1 - 3和LL37。转染ASK1-Δ N后，hBD 1 - 3和LL37在正常人角质形成细胞中的表达明显增强。此外，p38抑制剂消除了这种诱导，表明ASK1-p38调节hBD 1 - 3和LL37的表达。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通过在表皮分化过程中形成由hBD、LL37和TLR2组成的免疫屏障来调节皮肤的先天免疫。皮肤伤口闭合对于抵抗微生物病原体是必不可少的，角质形成细胞迁移是皮肤伤口愈合的重要步骤。由于LL-37在皮肤伤口部位上调，LL-37可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反式激活诱导角质形成细胞迁移。该研究强烈表明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

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

橋本公二: "皮膚科診療プラクティス"浅井 宏祐. 6 (2003)

桥本浩二：《皮肤科实践》浅井浩介 6 (2003)。

Handbook for skin immunology, Vol2, Innate Immunity (in Japanese).

皮肤免疫学手册，第 2 卷，先天免疫（日语）。

• 发表时间: 2005
• 作者: Takai Y;Britton KR et al.;Koji Sayama
• 通讯作者: Koji Sayama

Yamasaki K: "SOCS1/JAB and SOCS3/CIS3 negatively regulate the STATs signaling pathway in normal human epidermal keratinoctyes"J Invest Dermatol. 120. 571-580 (2003)

Yamasaki K：“SOCS1/JAB 和 SOCS3/CIS3 对正常人表皮角质细胞中的 STATs 信号通路负调节”J Invest Dermatol。

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