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The Role of TLR4-ligands S100A8/A9 and S100A12 in Familial Mediterranean Fever (FMF)

TLR4 配体 S100A8/A9 和 S100A12 在家族性地中海热 (FMF) 中的作用

基本信息

批准号：
262456452
负责人：
Privatdozent Dr. Helmut Wittkowski
金额：
--
依托单位：
Klinik für Rheumatologie und klinischen Immunologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2014
资助国家：
德国
起止时间：
2013-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/262456452?language=en
关键词：
Role TLR4 ligands S100A8 A9

项目摘要

Familial Mediterranean Fever (FMF) is an autoinflammatory syndrome associated with the activation of phagocytic cells and an oversecretion of the proinflammatory cytokine interleukin-1 beta. The discovery of pyrin mutations as the genetic basis of this autoinflammatory disorder opened up new avenues of research linking dysfunction of intracellular processes, e.g. alternative secretory pathways, and immune dysregulation involving inflammasome-dependent recruitment and processing of IL-1beta. However, the exact pathogenic mechanisms in FMF are still elusive. We have demonstrated that the phagocyte-derived Damage Associated Molecular Pattern (DAMP) proteins S100A8 and S100A9 as well as S100A12 are found at excessive concentrations in serum from FMF patients. These proteins are, as IL-1beta, released by alternative secretory pathways and exhibit pro-inflammatory effects through interaction with Pattern Recognition Receptors (PRRs). More specifically, S100A8 and S100A9 as well as S100A12 have been recently described as Toll-like receptor 4 (TLR-4) activators. The potential function of pyrin involved in phagocyte-specific S100-protein secretion, its relation to IL-1, and the reason for excessively high concentrations of these proteins in FMF have not been characterized to date. We hypothesize that mutated pyrin drives FMF pathophysiology via interaction with the cytoskeleton and alteration of secretory pathways, leading to high amounts of specific pro-inflammatory molecules like the phagocyte-specific S100-proteins. In order to investigate the role of S100-proteins in FMF, we propose to analyze their expression, secretion and pro-inflammatory functions in pyrin mutated mice (FMF mice) and in cell-lines transfected with constructs carrying the FMF pyrin mutation. Additionally, to examine the impact of S100-proteins on the pathogenesis of FMF in vivo, we plan to cross S100A9 deficient mice (S100A9-/- mice) and transgenic S100A12 overexpressing mice (S100A12-tg mice) with FMF mice to define the inflammatory phenotype of these animals.

家族性地中海热（FMF）是一种自身炎症综合征，与吞噬细胞的激活和促炎细胞因子白细胞介素-1 β的过度分泌有关。pyrin突变作为这种自身炎症性疾病的遗传基础的发现，开辟了新的研究途径，将细胞内过程的功能障碍联系起来，例如替代分泌途径，以及涉及炎性小体依赖性募集和il -1 β加工的免疫失调。然而，FMF的确切致病机制尚不清楚。我们已经证明，吞噬细胞衍生的损伤相关分子模式（DAMP）蛋白S100A8和S100A9以及S100A12在FMF患者的血清中浓度过高。这些蛋白，如il -1 β，通过其他分泌途径释放，并通过与模式识别受体（PRRs）相互作用表现出促炎作用。更具体地说，S100A8和S100A9以及S100A12最近被描述为toll样受体4 （TLR-4）激活剂。pyrin参与吞噬细胞特异性s100蛋白分泌的潜在功能，其与IL-1的关系，以及FMF中这些蛋白浓度过高的原因迄今尚未被表征。我们假设突变的pyrin通过与细胞骨架的相互作用和分泌途径的改变来驱动FMF的病理生理，导致大量的特异性促炎分子，如吞噬细胞特异性s100蛋白。为了研究s100蛋白在FMF中的作用，我们拟分析其在pyrin突变小鼠（FMF小鼠）和携带FMF pyrin突变构建体的细胞系中的表达、分泌和促炎功能。此外，为了研究s100蛋白在体内对FMF发病机制的影响，我们计划将S100A9缺陷小鼠（S100A9-/-小鼠）和转基因S100A12过表达小鼠（S100A12-tg小鼠）与FMF小鼠杂交，以确定这些动物的炎症表型。