Influence of tissue stress and -damage on the development of allergic contact dermatitis
组织应激和损伤对过敏性接触性皮炎发生的影响
基本信息
- 批准号:241277709
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:德国
- 项目类别:Research Grants
- 财政年份:2013
- 资助国家:德国
- 起止时间:2012-12-31 至 2017-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Allergic contact dermatitis (ACD) is a T cell mediated skin disease with increasing prevalence. While the mechanisms resulting in T cell activation are quite well understood, the initial reactions providing a pro-inflammatory milieu in the skin remain unknown. Neither causative treatments for ACD nor validated in vitro assays to safely identify contact sensitizers exist. We have shown that the induction of allergic responses in the murine contact hypersensitivity (CHS) model crucially depends on the induction of an pro-inflammatory cytokine milieu in the skin. Here, activation of innate immune responses via pattern recognition receptors, i.e. the Toll-like receptors 2 and 4, is involved. Production of endogenous ligands for the activation of these receptors is mediated by induction of reactive oxygen species and the degradation of the extracellular matrix component hyaluronic acid. Release of ATP and its activation of the NLRP3 inflammasome are also involved in this setting. Together, these findings indicate that contact sensitizers induce tissue stress and damage as an essential element of the induction of CHS. However, the underlying mechanisms remain unknown so far. In this proposal we will investigate the effect of contact sensitizers and irritants on the induction of tissue stress and damage responses. We hypothesize that contact sensitizers are able to induce the activation of the unfolded protein response (UPR), autophagy, apoptosis and necrosis and that these responses are involved in the essential innate inflammatory response. Our preliminary data shows that the contact sensitizer trinitrochlorobenzene is able to induce the splicing of XBP-1, thus activating an important mediator of the UPR signaling cascade. As it is not known if the signaling pathway activated downstream of the UPR is the same for contact sensitizers and irritants, analysis of these pathways will not only add to our understanding of the mechansims leading to ACD but might also enable a differentiation between sensitizers and irritants in an in vitro setting. Analysis of these pathways might allow us to understand the underlying differences between strong and weak contact sensitizers and interference with these pathways should result in a reduction of inflammation thus abrogating CHS responses. This assumption is strengthened by our preliminary data showing that application of smac mimetica (inhibitors of the IAPs (IAP=inhibitor of apoptosis proteins)) is able to inhibit the CHS response to contact sensitizer treatment. The proposed project will identify potential targets for therapeutic interference as well as provide the basis for the development of urgently needed novel in vitro assays with mechanisitically defined endpoints for contact allergen identification.
变态反应性接触性皮炎(ACD)是一种由T细胞介导的皮肤病,发病率呈上升趋势。虽然导致T细胞激活的机制已经非常清楚,但在皮肤中提供促炎环境的最初反应仍不清楚。既没有ACD的病因治疗,也没有安全鉴定接触性致敏剂的体外试验。我们已经证明,在小鼠接触性超敏(CHS)模型中,过敏反应的诱导关键取决于皮肤中促炎细胞因子环境的诱导。在这里,涉及到通过模式识别受体,即Toll样受体2和4来激活先天免疫反应。激活这些受体的内源性配体的产生是通过诱导活性氧物种和降解细胞外基质成分透明质酸来调节的。ATP的释放及其对NLRP3炎症小体的激活也参与了这一过程。综上所述,这些发现表明,接触性增敏剂诱导组织应激和损伤是诱发CHS的一个重要因素。然而,到目前为止,潜在的机制仍然不清楚。在这项提案中,我们将研究接触敏化剂和刺激物对组织应力和损伤反应的诱导作用。我们假设接触性致敏剂能够诱导未折叠蛋白反应(UPR)的激活、自噬、细胞凋亡和坏死,这些反应与必要的先天炎症反应有关。我们的初步数据显示,接触敏化剂三硝基氯苯能够诱导XBP-1的剪接,从而激活UPR信号级联的一个重要中介。由于目前尚不清楚UPR下游激活的信号通路是否与接触性致敏剂和刺激物相同,因此对这些通路的分析不仅有助于我们理解ACD的发病机制,还可能在体外实验中区分致敏剂和刺激物。对这些途径的分析可能会让我们了解强接触和弱接触致敏剂之间的潜在差异,对这些途径的干扰应该会导致炎症的减少,从而消除CHS反应。我们的初步数据证实了这一假设,该数据表明,应用Smac Mimetica(IAP抑制物(IAP))能够抑制CHS对接触敏化剂治疗的反应。拟议的项目将确定潜在的治疗干预目标,并为开发迫切需要的新型体外检测方法提供基础,该方法具有用于接触性变应原鉴定的机械定义的终点。
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Absence of the Integrin α3 Subunit Induces an Activated Phenotype in Human Keratinocytes.
整合素 α3 亚基的缺失会诱导人类角质形成细胞激活表型
- DOI:10.1016/j.jid.2017.01.018
- 发表时间:2017
- 期刊:
- 影响因子:0
- 作者:Busch H;Esser P;Kiritsi D;Gache Y;Bruckner-Tuderman L;Boerries M;Has C.
- 通讯作者:Has C.
Chemical Allergen‐Induced Skin Cell Activation
化学过敏原诱导的皮肤细胞活化
- DOI:10.1002/9783527676965.ch5
- 发表时间:2014
- 期刊:
- 影响因子:0
- 作者:Martin S.F;Esser P.R.
- 通讯作者:Esser P.R.
Epithelial stress and contact dermatitis
上皮应激和接触性皮炎
- DOI:10.1016/j.toxlet.2015.08.116
- 发表时间:2015
- 期刊:
- 影响因子:3.5
- 作者:Martin S.F;Esser P.R.
- 通讯作者:Esser P.R.
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