Identification and characterization of the mechanisms and relevance of inflammasome activation in mast cells

肥大细胞炎症小体激活机制和相关性的鉴定和表征

基本信息

项目摘要

Traditionally, mast cells (MCs) are seen mainly as effector cells of the adaptive immune system, since they can mediate anaphylactic reactions upon allergen-induced IgE crosslinking. However, MCs are emerging as key contributors to innate immune responses: They express a large repertoire of innate immune signaling receptors, including most members of the Toll-like receptor (TLR) family, Rig-I like receptors and Nod-like receptors. Similar to macrophages and dendritic cells, MCs can be activated by danger signals derived from pathogens, and they can sense altered host molecules that appear during tissue damage. Inflammasomes are an important class of innate immunity sensors for such danger signals. Via Interleukin 1 beta (IL-1 beta), they drive early inflammatory responses during tissue damage by sensing many endogenous molecules that are altered by cell stress or mislocalized during bacterial infection. Many prevalent diseases in Western societies, including chronic obstructive pulmonary disease, metabolic syndrome, atherosclerosis and Alzheimer disease are influenced by erroneous activation of inflammasomes such as NLRP3, which is now considered a promising therapeutic target. Recent studies have highlighted the importance of MC inflammasome activation for the development of skin lesions in patients with autoinflammatory conditions. The importance of MC inflammasome activation beyond these conditions has so far not been studied. Chronic wounds, complicated by bacterial superinfection, present an increasing medical and economic burden with an incidence of 2% in aging Western societies. Chronic wound infections are associated with increased activation of mast cells and inflammasome mediators such as IL-1 beta. UV-irradiation is a sterile inflammasome activator and causes MC-mediated inflammation that is linked to the development of melanoma. We are, therefore, interested in studying the connection between MCs and inflammasome activation in these two conditions. Our preliminary data show that human and mouse MCs express a wide range of functional inflammasomes and that they respond towards inflammasome stimuli independently of histamine release. We, here, propose to study the pathways of inflammasome activation in MC-dependent models of inflammation with the help of an inflammasome reporter mouse (m-ASC-cerulean). Secondly, we will reconstitute MC-deficient mice selectively with MCs that lack different inflammasomes to identify the role of specific inflammasomes in disease development. We will then assess the relevance of MC inflammasome activation in human skin inflammation. Finally, as a proof of principle, we will test the effect of small molecules identified by high throughput screens as inflammasome activation mosulators on MCs. We thereby aim to swiftly translate our findings and generate new therapeutic perspectives for MC- and inflammasome-related skin diseases.
传统上,肥大细胞(MCs)主要被视为适应性免疫系统的效应细胞,因为它们可以介导过敏性反应过敏原诱导的IgE交联。然而,MC正在成为先天免疫应答的关键贡献者:它们表达大量先天免疫信号受体,包括Toll样受体(TLR)家族的大多数成员、Rig-I样受体和Nod样受体。与巨噬细胞和树突状细胞类似,MC可以被来自病原体的危险信号激活,并且它们可以感知组织损伤期间出现的改变的宿主分子。炎性小体是这种危险信号的一类重要的先天免疫传感器。通过白细胞介素1 β(IL-1 β),它们通过感知许多在细菌感染期间被细胞应激改变或错误定位的内源性分子,在组织损伤期间驱动早期炎症反应。在西方社会,许多流行的疾病,包括慢性阻塞性肺疾病,代谢综合征,动脉粥样硬化和阿尔茨海默病的影响,如NLRP 3,这是现在被认为是一个有前途的治疗靶点的炎性小体的错误激活。最近的研究强调了MC炎性小体激活对自身炎性疾病患者皮肤病变发展的重要性。MC炎性小体激活超过这些条件的重要性迄今尚未研究。慢性伤口,并发细菌二重感染,提出了一个日益增加的医疗和经济负担,发病率为2%,在老龄化的西方社会。慢性伤口感染与肥大细胞和炎性体介质如IL-1 β的活化增加有关。紫外线照射是一种无菌炎性小体激活剂,可引起MC介导的炎症,与黑色素瘤的发生有关。因此,我们有兴趣研究这两种情况下MC和炎性小体激活之间的联系。我们的初步数据表明,人类和小鼠MCs表达广泛的功能性炎性小体,它们对炎性小体刺激的反应独立于组胺的释放。在这里,我们建议在炎性小体报告小鼠(m-ASC-天蓝色)的帮助下研究MC依赖性炎症模型中炎性小体激活的途径。其次,我们将选择性地用缺乏不同炎性小体的MC重建MC缺陷小鼠,以确定特定炎性小体在疾病发展中的作用。然后,我们将评估MC炎性小体激活在人类皮肤炎症中的相关性。最后,作为原理的证明,我们将测试通过高通量筛选鉴定的小分子作为炎性小体激活因子对MC的影响。因此,我们的目标是迅速转化我们的研究结果,并为MC和炎性小体相关的皮肤疾病产生新的治疗前景。

项目成果

期刊论文数量(2)
专著数量(0)
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会议论文数量(0)
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Professor Dr. Marcus Maurer其他文献

Professor Dr. Marcus Maurer的其他文献

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{{ truncateString('Professor Dr. Marcus Maurer', 18)}}的其他基金

Identification and characterization of mast cell functions in Sporothrix schenckii infections
申克孢子丝菌感染中肥大细胞功能的鉴定和表征
  • 批准号:
    242029477
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Digital knowledge gaps. The dissemination, use, and processing of information in the online world
数字知识差距。
  • 批准号:
    189887938
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
    Research Units
Generation of breeders for setting up mutant mouse colonies by priority programme members
由优先计划成员培育用于建立突变小鼠群体的育种者
  • 批准号:
    125522718
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
    Priority Programmes
Identifizierung der Mechanismen und Charakterisierung der allergologischen, immunologischen und klinischen Relevanz der Induktion von Toleranz gegenüber Kontaktallergenen
识别接触性过敏原耐受诱导的过敏学、免疫学和临床相关性的机制和特征
  • 批准号:
    58181023
  • 财政年份:
    2008
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Mechanisms of mast cell activation and function in natural immunity to bacteria
肥大细胞激活机制及其在细菌自然免疫中的功能
  • 批准号:
    5357782
  • 财政年份:
    2002
  • 资助金额:
    --
  • 项目类别:
    Priority Programmes
Characterization of the Prevalence, Immunologic Features, and Clinical Implications of Autoimmune Subtypes of Chronic Spontaneous Urticaria (CAS-CSU)
慢性自发性荨麻疹 (CAS-CSU) 自身免疫亚型的患病率、免疫学特征和临床意义的表征
  • 批准号:
    464568473
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
    Research Grants
B04: Analysis of the Accuracy and Comprehensibility of Media Content Used by Medical and Economics Students in Higher Education Online Learning Settings
B04:高等教育在线学习环境中医学和经济学学生使用的媒体内容的准确性和可理解性分析
  • 批准号:
    520634386
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
    Research Units
Constructive journalism. Empirical analyses of the potential effects of a new form of journalism
建设性的新闻报道。
  • 批准号:
    512131520
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
    Research Grants

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酒精使用障碍和过量饮酒的新遗传机制的鉴定和表征
  • 批准号:
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    2022
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  • 批准号:
    10399924
  • 财政年份:
    2021
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    --
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Identification and Characterization of Novel Genetic Mechanisms in Alcohol Use Disorder and Excessive Drinking
酒精使用障碍和过量饮酒的新遗传机制的鉴定和表征
  • 批准号:
    10018802
  • 财政年份:
    2019
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Identification and Characterization of Novel Genetic Mechanisms in Alcohol Use Disorder and Excessive Drinking
酒精使用障碍和过量饮酒的新遗传机制的鉴定和表征
  • 批准号:
    9806313
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Identification and Characterization of Genes Required for Listeria monocytogenes Cytosolic Survival
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    10164969
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    2018
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Whole genome identification and characterization of novel mechanisms of resistance to topoisomerase-targeting drugs in protozoan parasites
原生动物寄生虫拓扑异构酶靶向药物耐药新机制的全基因组鉴定和表征
  • 批准号:
    528731-2018
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    2018
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    Alexander Graham Bell Canada Graduate Scholarships - Master's
Identification and Characterization of Genes Required for Listeria monocytogenes Cytosolic Survival
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  • 批准号:
    10463622
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Identification and Characterization of Genes Required for Listeria monocytogenes Cytosolic Survival
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