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

全世界超过十分之一的成年人患有慢性肾脏疾病(CKD)。这种高发病率和缺乏适当的治疗方法，要求开发新的治疗策略。去调节的无菌炎症和细胞外基质(ECM)的积聚是肾脏纤维化的重要触发因素和慢性肾脏疾病的组成部分。到目前为止，负责将无菌炎症转换为消退或同步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，是炎症性肾脏疾病潜在的重要调节因子。值得注意的是，越来越多的证据表明，感染性和无菌炎症的严重程度与促炎血单核细胞数量的增加有关，这些血单核细胞主要由中间和非典型单核细胞组成。然而，触发单核细胞从经典亚群切换到中间亚群和非经典亚群的机制仍然不清楚。尽管单核细胞在CKD的调控中具有潜在的重要性，但关于单核细胞亚型在炎症性肾病发病中的作用及其对疾病的影响的数据尚不清楚。在以前的研究中，PI实验室已经发现了两种可溶性蛋白多糖，即Biglycan和Decorin，它们是天然免疫受体Toll样受体(TLR)4和TLR2的内源性配体。此外，我们还在感染性和无菌炎症患者的血清中检测到了可溶性二聚糖。我们新的初步数据表明，Biglycan通过与TLR2/4的接头分子CD14相互作用影响单核细胞表型，从而诱导向中间和非经典单核细胞的转变。基于这些新的发现，我们计划确定血清中可溶性胆聚糖/核心蛋白的来源和生物学功能，特别关注蛋白多糖诱导的单核细胞表型的变化及其对肾脏炎症和纤维化的影响。最终目的是通过中和抗体/肽阻止双聚糖与单核细胞上CD14/TLR2/4的结合，为控制炎症性肾脏疾病和纤维化的慢性化提供新的治疗方法的原理证据。

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.