Mast cell Stat5-regulatory pathway in atopic dermatitis

特应性皮炎中肥大细胞 Stat5 调节通路

• 批准号: 9042923
• 负责人: TOSHIAKI KAWAKAMI
• 金额: $ 38.94万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9042923
• 关键词: Adult; Adverse effects; Affinity; Allergens; Allergic Disease; Asthma; Atopic Dermatitis; Biology; C-terminal; Calcineurin inhibitor; Cells; Child; Chronic; Clinical; Complex; Confocal Microscopy; Data; Dependency; Dermal; Dermatitis; Developed Countries; Development; Disease; Elements; Environmental Risk Factor; Etiology; Exhibits; Fibroblasts; Gene Components; Gene Expression; Gene Expression Profiling; Genes; Genetic; Growth; Health; Human; IgE Receptors; In Vitro; Individual; Inflammation; Inflammatory; Knockout Mice; Knowledge; Link; Mediating; Modeling; Molecular; Molecular Profiling; Mus; PTPN6 gene; Paper; Pathogenesis; Patients; Pharmaceutical Preparations; Phospholipase C; Phosphorylation; Phosphotransferases; Pimecrolimus; Play; Polymorphism Analysis; Prevalence; Preventive; Production; Protein phosphatase; Receptor Cell; Regulation; Regulatory Pathway; Reporting; Risk; Role; STAT protein; Severities; Signal Transduction; Single Nucleotide Polymorphism; Skin; Staphylococcal Enterotoxin B; Stat3 protein; Stat5 protein; Steroids; TSLP gene; Tacrolimus; Therapeutic; Wild Type Mouse; bone marrow hyperplasia; cytokine; immune function; in vivo; in vivo Model; inhibitor/antagonist; innovation; keratinocyte; mast cell; mouse model; novel; novel therapeutic intervention; novel therapeutics; periostin; prevent; protein complex; receptor; research study; skin barrier; skin disorder; skin lesion; src Homology Region 2 Domain; transcription factor

DESCRIPTION (provided by applicant): Atopic dermatitis (AD) is a chronic pruritic inflammatory skin disease with an increasing prevalence. Although the etiology of AD is not completely understood, numerous studies suggest that impaired skin barrier function and immune dysregulation underlie the disease. We have developed novel allergen-inducible and spontaneous mouse models that mimic human AD: AD-like skin lesions induced by epicutaneous treatment with allergen require mast cells and the receptor for thymic stromal lymphopoietin (TSLP). We found that phospholipase C (PLC)-¿3-deficient mice spontaneously develop AD-like skin lesions with increased expression of TSLP and periostin in a mast cell-dependent manner; allergen-induced dermatitis was more severe in PLC-¿3-/- than in wild-type mice. Gene expression profiles in lesional skin exhibited high similarity between allergen-induced dermatitis, spontaneous dermatitis in PLC-¿3-/- mice, and human AD. We recently reported that PLC-¿3 inhibits the proliferation of hematopoietic cells, including mast cells, through formation of the multi-molecular SPS complex containing SHP-1 (protein phosphatase), PLC-¿3, and Stat5 (transcription factor); PLC-¿3 interacts with SHP-1 and Stat5, augments the dephosphorylating activity of SHP-1 toward Stat5, and inhibits Stat5 activity. Stat5 and Jak2 (a Stat5-activating kinase) are essential for the development and proliferation of mast cells. Our preliminary data indicated the involvement of mast-cell Stat5 and SHP-1 in AD pathogenesis, as revealed by reduced or enhanced severity of allergen-induced dermatitis in mice with mast cell-specific deletion of Stat5 or SHP-1, respectively, as well as strong efficacy of a Jak-Stat5 inhibitor to prevent allergen-induced dermatitis. Moreover, human AD skin had increased numbers of mast cells with high activation levels of STAT5 and the genes encoding the SPS components were linked to the risk of human AD and/or its severity. These and other preliminary data have led to the following hypotheses: (1) The Stat5- regulatory pathway in mast cells plays a critical pathogenic role in AD. (2) SPS components regulate the activity of the cellular elements of the dermatitis-amplifying/perpetuating vicious cycle consisting of Th2 cytokines (mast cells), periostin (fibroblasts), and TSLP (keratinocytes). (3) The SPS components regulate not only mouse, but also human mast cell biology. Therefore, (Aim 1) using conditional knockout mice of SPS component genes as well as pharmacological approaches, we will further evaluate the role of the mast cell Stat5-regulatory pathway in development and persistence of dermatitis in PLC-¿3-/- mice. (Aim 2) Using in vitro cultures and in vivo models, we will study how SPS components regulate Th2 cytokine production from mast cells, periostin production from fibroblasts, and TSLP production from keratinocytes. (Aim 3) Finally, we will study the role of SPS components in the growth, survival, and Fc?RI (high-affinity IgE receptor)-mediated activation of human mast cells and compare mast cells between human AD and healthy individuals. Overall, this project will likely establish a novel paradigm of AD pathogenesis and provide a novel therapeutic strategy.

描述（由申请人提供）：特应性皮炎（AD）是一种慢性皮炎性炎症性皮肤病，患病率不断增加。虽然AD的病因尚未完全清楚，但许多研究表明，皮肤屏障功能受损和免疫失调是该疾病的基础。我们已经开发了新的过敏原诱导和自发的小鼠模型，模仿人类AD：AD样皮肤病变引起的表皮治疗过敏原需要肥大细胞和胸腺基质淋巴细胞生成素（TSLP）的受体。我们发现，磷脂酶C（PLC）-<$3-缺陷小鼠自发发展AD样皮肤病变，TSLP和骨膜蛋白的表达增加，肥大细胞依赖性的方式;过敏原诱导的皮炎PLC-<$3-/-比野生型小鼠更严重。病变皮肤中的基因表达谱在变应原诱导的皮炎、PLC-<$3-/-小鼠的自发性皮炎和人类AD之间表现出高度相似性。我们最近报道PLC-<$3通过形成包含SHP-1（蛋白磷酸酶）、PLC-<$3和Stat 5（转录因子）的多分子SPS复合物来抑制造血细胞（包括肥大细胞）的增殖; PLC-<$3与SHP-1和Stat 5相互作用，增强SHP-1对Stat 5的去磷酸化活性，并抑制Stat 5活性。Stat 5和Jak 2（Stat 5活化激酶）对于肥大细胞的发育和增殖是必需的。我们的初步数据表明肥大细胞Stat 5和SHP-1参与AD发病机制，如肥大细胞特异性缺失Stat 5或SHP-1的小鼠中变应原诱导的皮炎的严重程度分别降低或增强所揭示的，以及Jak-Stat 5抑制剂预防变应原诱导的皮炎的强大功效。此外，人类AD皮肤具有增加数量的具有高活化水平的STAT 5的肥大细胞，并且编码SPS组分的基因与人类AD的风险和/或其严重程度相关。这些和其他初步数据导致了以下假设：（1）肥大细胞中的Stat 5调节通路在AD中起着关键的致病作用。(2)SPS组分调节皮炎-扩增/持续恶性循环的细胞成分的活性，所述恶性循环由Th 2细胞因子（肥大细胞）、骨膜蛋白（成纤维细胞）和TSLP（角质形成细胞）组成。(3)SPS组分不仅调节小鼠，而且调节人肥大细胞生物学。因此，（目的1）使用SPS组分基因的条件性敲除小鼠以及药理学方法，我们将进一步评估肥大细胞Stat 5调节途径在PLC-<$3-/-小鼠皮炎发展和持续性中的作用。(Aim 2）利用体外培养和体内模型，我们将研究SPS组分如何调节肥大细胞产生的Th 2细胞因子、成纤维细胞产生的骨膜蛋白和角质形成细胞产生的TSLP。(Aim 3）最后，我们将研究SPS组分在生长、存活和Fc？RI（高亲和力IgE受体）介导的人肥大细胞活化，并比较人AD和健康个体之间的肥大细胞。总体而言，该项目可能会建立一个新的范式AD发病机制，并提供一个新的治疗策略。