Trim32 Regulation of Piasy in Skin Homeostasis

Trim32 对 Piasy 皮肤稳态的调节

• 批准号: 8060575
• 负责人: MOLLY F. KULESZ-MARTIN
• 金额: $ 32.93万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8060575
• 关键词: 19p13; Acanthosis; Apoptosis; Apoptotic; Atopic Dermatitis; CCL20 gene; CCR6 gene; Cell Survival; Cells; Chromosomes; Death Rate; Dendritic Cells; Dermal; Development; Disease; Environment; Enzymes; Epidermis; Equilibrium; Feedback; Fostering; Genes; Growth; Health; Homeostasis; Human; Hyperplasia; IL17 gene; ITGAX gene; Immune; Immune system; In Vitro; Infiltration; Inflammation; Inflammatory; Interleukin-17; Knockout Mice; Lead; Lesion; Ligase; Link; Lymphocyte; Mediating; Modeling; Molecular; Mus; NF-kappa B; Organ; Parakeratosis; Partner in relationship; Pathogenesis; Pathway interactions; Patients; Phenotype; Predisposition; Production; Proteins; Psoriasiform Dermatitis; Psoriasis; Regulation; Role; Severities; Skin; Symptoms; TNF gene; Testing; Th2 Cells; Therapeutic; Tissue Sample; Transgenic Mice; Up-Regulation; base; chemokine; cytokine; human disease; in vivo; inhibitor/antagonist; interleukin-22; interleukin-23; keratinocyte; mouse model; response; skin disorder; transcription factor; treatment strategy; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): There is a vicious circle in psoriasis that disrupts epidermal homeostasis through alterations in keratinocytes (hyperproliferation, parakeratosis) and immunocytes (infiltration and activation). While it is well known that uncontrolled keratinocyte proliferation is largely driven by pro-inflammatory cytokines from the immunocytes, the functional role of keratinocytes in the recruitment and activation of immunocytes is poorly understood. We have discovered intriguing links between Trim32 (an E3 ubiquitin ligase), its substrate Piasy (an E3 SUMO ligase), and psoriasis. Trim32 is elevated in psoriasis tissue samples compared to non-lesional control epidermis. Trim32 negatively regulates the pro-apoptotic Piasy protein, a repressor of NF-kB, STAT, and SMAD transcription factors that have been implicated in the pathogenesis of psoriasis. The Piasy gene resides in the PSORS6 susceptibility locus on chromosome 19p13, although the significance of this remains to be determined. We have found that Trim32 activates and Piasy inhibits keratinocyte production of CCL20, a chemokine increased in psoriatic lesions that is a major factor in recruitment of dendritic cells and Th17 lymphocytes to the skin. The CCL20 induction by TNFa and IL17 cytokines is mediated through the activation of NF-kB. These findings lead us to hypothesize that Trim32 and Piasy are part of a positive feedback loop of CCL20 overproduction by keratinocytes and Th17 activation that contributes to the cycle of psoriasis. Initial evidence suggests that Trim32 is not simply a general marker of epidermal hyperplasia because its elevation in psoriasis, recognized as a Th17 disease, is not shared by atopic dermatitis, recognized as a Th2 cell disease, and because upregulation of CCL20 in keratinocytes responds to Th17 but not Th1 or Th2 cytokines. We propose to define the role of Trim32 and Piasy in psoriasis according to the following aims: 1) determine molecular pathways of Trim32 and Piasy regulation of CCL20 production in keratinocytes in response to Th17 cytokines, in particular through the NF-kB pathway, and evaluate the effects of Trim32 and Piasy on the dermal recruitment of CD11c+ dendritic cells and Th17 cells; 2) explore the functional role of Trim32 and Piasy in keratinocyte survival and epidermal acanthosis in response to Th17 activation, using in vitro and in vivo approaches, and determine the impact of Trim32 KO and Piasy KO on the severity of phenotypes in two mouse models of psoriasiform dermatitis; and 3) evaluate the role of Trim32 and Piasy in CCL20 expression, inflammation and keratinocyte apoptosis in psoriasis and atopic dermatitis. Ultimately, these studies may impact our understanding of the molecular mechanisms of psoriasis as distinct from atopic dermatitis and lead to rational improvement of treatment strategies for psoriasis patients. PUBLIC HEALTH RELEVANCE: Psoriasis is a skin disease in which skin cells lose the proper balance between their growth and death rates, and certain immune system cells are over-active. We have found that the enzyme "Trim32" is overly active in psoriasis, causing loss of the protein Piasy, a major inhibitor of certain genes that are active in human psoriasis and that can cause psoriasis-like symptoms in mice, leading to the production of proteins that attract more immune cells to the skin, making the symptoms worse. Understanding how Trim32 and Piasy control skin cell survival and skin inflammation promises new ways to treat psoriasis and other human diseases of the skin, as well as inflammatory diseases in other organs of the body.

描述（由申请人提供）：牛皮癣存在恶性循环，通过角化细胞（增生、角化不全）和免疫细胞（浸润和激活）的改变破坏表皮稳态。众所周知，不受控制的角化细胞增殖主要是由免疫细胞的促炎细胞因子驱动的，但角化细胞在免疫细胞募集和激活中的功能作用却知之甚少。我们已经发现了Trim32 （E3泛素连接酶）及其底物Piasy （E3 SUMO连接酶）与牛皮癣之间的有趣联系。与非病变对照表皮相比，Trim32在牛皮癣组织样本中升高。Trim32负性调节促凋亡Piasy蛋白，该蛋白是NF-kB、STAT和SMAD转录因子的抑制因子，与牛皮癣的发病机制有关。Piasy基因位于19p13染色体上的PSORS6易感位点，尽管其意义仍有待确定。我们发现Trim32激活和Piasy抑制角化细胞CCL20的产生，CCL20是银屑病病变中增加的趋化因子，是树突状细胞和Th17淋巴细胞向皮肤募集的主要因素。tnf - fa和il - 17细胞因子诱导CCL20是通过活化NF-kB介导的。这些发现使我们假设Trim32和Piasy是角质形成细胞过量产生CCL20和Th17激活的正反馈循环的一部分，这有助于牛皮癣的循环。初步证据表明，Trim32不仅仅是表皮增生的一般标记物，因为其在牛皮癣（被认为是Th17疾病）中的升高并不存在于特应性皮炎（被认为是Th2细胞疾病）中，并且因为角化细胞中CCL20的上调对Th17有反应，而对Th1或Th2细胞因子没有反应。我们拟根据以下目的确定Trim32和Piasy在银屑病中的作用：1)确定Trim32和Piasy在响应Th17细胞因子的角质形成细胞中调节CCL20产生的分子途径，特别是通过NF-kB途径，评估Trim32和Piasy对CD11c+树突状细胞和Th17细胞真皮募集的影响；2)采用体外和体内两种方法，探讨Th17激活时Trim32和Piasy在角化细胞存活和表皮棘层中的功能作用，并确定Trim32 KO和Piasy KO对两种银屑病样皮炎小鼠模型表型严重程度的影响；3)评价Trim32和Piasy在银屑病和特应性皮炎患者CCL20表达、炎症和角化细胞凋亡中的作用。最终，这些研究可能会影响我们对银屑病不同于特应性皮炎的分子机制的理解，并导致银屑病患者治疗策略的合理改进。公共卫生相关性：牛皮癣是一种皮肤疾病，皮肤细胞在其生长和死亡率之间失去适当的平衡，某些免疫系统细胞过度活跃。我们发现，“Trim32”酶在牛皮癣中过度活跃，导致Piasy蛋白的丧失，Piasy蛋白是人类牛皮癣中活跃的某些基因的主要抑制剂，可以在小鼠中引起牛皮癣样症状，导致蛋白质的产生，吸引更多免疫细胞到皮肤上，使症状恶化。了解Trim32和Piasy如何控制皮肤细胞存活和皮肤炎症，有望为治疗牛皮癣和其他人类皮肤疾病以及身体其他器官的炎症性疾病提供新的方法。