Molecular mechanisms of monocyte modulation by soluble proteoglycans and their impact on inflammatory renal diseases

可溶性蛋白聚糖调节单核细胞的分子机制及其对炎症性肾病的影响

• 批准号: 280926947
• 负责人: Professorin Dr. Liliana Schaefer
• 金额: --
• 依托单位: Institut für Allgemeine Pharmakologie und Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/280926947?language=en
• 关键词: Molecular; mechanisms; monocyte; modulation; soluble

More than one in ten adults world wide experience chronic renaldiseases (CKD). This high incidence together with lack of appropriatecurative treatments, call for the development of novel therapeuticstrategies. Deregulated sterile inflammation and accumulation ofextracellular matrix (ECM) are important triggers of renal fibrogenesisand components of chronic renal diseases. So far, the mechanismsresponsible for switching sterile inflammation to resolution orchronification have remained elusive. Monocytes from peripheralblood as precursor cells of renal macrophages and dendritic cells arepotential crucial regulators of inflammatory kidney diseases. Notably,there is mounting evidence linking the severity of infectious and sterileinflammation to enhanced number of proinflammatory bloodmonocytes, mostly comprised of intermediate and non-classicalmonocytes. However the mechanisms triggering the monocyte switchfrom classical to intermediate and non-classical subsets remainelusive. Despite of potential importance of monocytes in theregulation of CKD data regarding the role of monocyte-subtypes atthe onset of inflammatory renal diseases and their impact on diseasechronification are missing. In previous studies, the PI laboratory hasdiscovered that two soluble proteoglycans, biglycan and decorin, actas endogenous ligands of innate immunity receptors Toll-like receptor(TLR)4 and TLR2. Furthermore, we detected soluble biglycan in theserum of patients with infectious and sterile inflammation. Our newpreliminary data indicate that biglycan influences monocytephenotypes by interacting with CD14, an adaptor molecule of TLR2/4,thereby inducing a shift towards intermediate and non-classicalmonocytes. Based on these novel findings we plan to identify sourcesand biological functions of soluble biglycan/decorin in serum withspecial attention to proteoglycan-induced changes in the phenotypesof monocytes and their impact on renal inflammation and fibrosis. Theultimate goal is to provide a proof-of-principle for novel therapeuticsaimed at controlling chronification of inflammatory renal diseases andfibrosis using neutralizing antibodies/peptides that prevent binding ofbiglycan to CD14/TLR2/4 on monocytes.

全世界超过十分之一的成年人患有慢性肾病 (CKD)。这种高发病率加上缺乏适当的治疗方法，需要开发新的治疗策略。失调的无菌炎症和细胞外基质（ECM）的积累是肾纤维发生和慢性肾病的重要触发因素。到目前为止，负责将无菌性炎症转变为消退或慢性化的机制仍然难以捉摸。来自外周血的单核细胞作为肾巨噬细胞和树突状细胞的前体细胞是炎症性肾病的潜在关键调节因子。值得注意的是，越来越多的证据表明，感染性和无菌性炎症的严重程度与促炎性血单核细胞数量的增加有关，其中促炎性血单核细胞主要由中间单核细胞和非经典单核细胞组成。然而，触发单核细胞从经典亚群转变为中间亚群和非经典亚群的机制仍然难以捉摸。尽管单核细胞在 CKD 调节中具有潜在重要性，但有关单核细胞亚型在炎症性肾病发作时的作用及其对疾病慢性化的影响的数据仍然缺失。 PI实验室在前期研究中发现，双糖链蛋白聚糖和核心蛋白聚糖这两种可溶性蛋白聚糖是先天免疫受体Toll样受体（TLR）4和TLR2的内源性配体。此外，我们在感染性和无菌性炎症患者的血清中检测到可溶性双糖链蛋白聚糖。我们的新初步数据表明，双糖链蛋白聚糖通过与 TLR2/4 的接头分子 CD14 相互作用来影响单核细胞表型，从而诱导向中间和非经典单核细胞的转变。基于这些新发现，我们计划确定血清中可溶性双糖链蛋白聚糖/核心蛋白聚糖的来源和生物学功能，特别关注蛋白聚糖诱导的单核细胞表型变化及其对肾脏炎症和纤维化的影响。最终目标是为旨在利用中和抗体/肽阻止双糖链蛋白聚糖与单核细胞上的 CD14/TLR2/4 结合来控制炎症性肾病和纤维化慢性化的新型疗法提供原理验证。

项目成果

Biglycan, a novel trigger of Th1 and Th17 cell recruitment into the kidney.

• DOI: 10.1016/j.matbio.2017.12.002
• 发表时间: 2017-12
• 期刊: Matrix biology : journal of the International Society for Matrix Biology
• 作者: M. Nastase;Jinyang Zeng-Brouwers;J. Beckmann;Claudia Tredup;U. Christen;H. Radeke;M. Wygrecka;L. Sc

A novel biological function of soluble biglycan: Induction of erythropoietin production and polycythemia

• DOI: 10.1007/s10719-016-9722-y
• 发表时间: 2017-06-01
• 期刊: GLYCOCONJUGATE JOURNAL
• 影响因子: 3
• 作者: Frey, Helena;Moreth, Kristin;Schaefer, Liliana
• 通讯作者: Schaefer, Liliana

Bimodal role of NADPH oxidases in the regulation of biglycan-triggered IL-1β synthesis.

• DOI: 10.1016/j.matbio.2015.12.005
• 发表时间: 2016-01
• 期刊: Matrix biology : journal of the International Society for Matrix Biology
• 作者: Hsieh LT;Frey H;Nastase MV;Tredup C;Hoffmann A;Poluzzi C;Zeng-Brouwers J;Manon-Jensen T;Schröder K;Brandes RP;Iozzo RV;Schaefer L
• 通讯作者: Schaefer L