LRG1: an emerging player in disease pathogenesis.
LRG1: an emerging player in disease pathogenesis.
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LRG1：疾病发病机理的新兴参与者。
DOI：
10.1186/s12929-022-00790-6
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发表时间：
2022-01-21
影响因子：
11
通讯作者：
Greenwood J
中科院分区：
文献类型：
--
作者：
Camilli C;Hoeh AE;De Rossi G;Moss SE;Greenwood J
分泌的富含亮氨酸的α-2糖蛋白1 （LRG1）在近十年前首次被描述为在致病性眼部新生血管中起关键作用。从那时起，越来越多的出版物报道了LRG1参与多种人类疾病，包括癌症、糖尿病、心血管疾病、神经系统疾病和炎症性疾病。本综述的目的是首次全面综述考虑其在健康和疾病中的作用的LRG1文献。尽管LRG1在肝细胞和中性粒细胞中组成性表达，但LRG1−/−小鼠没有表现出明显的表型异常，这表明LRG1在发育和体内平衡中基本上是多余的。然而，新出现的数据通过提出LRG1在先天免疫和组织完整性保护中的新作用来挑战这一观点。虽然我们对LRG1在生理上的有益功能的了解仍然有限，但一致的证据表明，在对各种炎症刺激的反应中，LRG1的表达被诱导并直接参与疾病的发病机制。在剖析LRG1致病功能的机制的同时，它作为多种疾病的诊断、预后和监测的生物标志物的潜在作用被广泛讨论。重点是LRG1作为血管病变因子的作用，它破坏了成熟血管形成和维持所需的细胞相互作用，从而间接促成了高度缺氧和免疫抑制微环境的建立。此外，LRG1也被报道影响其他细胞类型（包括上皮细胞、免疫细胞、间充质细胞和癌细胞），主要是通过以上下文依赖的方式调节tgf - β信号通路。至关重要的是，动物研究表明，通过基因缺失或功能阻断抗体抑制LRG1足以减缓疾病进展。鉴于此，并考虑到其作为tgf - β信号传导上游调节剂的作用，LRG1被认为是一个潜在的重要治疗靶点。虽然需要进一步的研究来填补我们目前对LRG1功能的理解空白，但本文综述的研究证实LRG1是一种多效性和致病性信号分子，为其在临床中作为生物标志物和治疗靶点提供了强有力的理论依据。
The secreted glycoprotein leucine-rich α-2 glycoprotein 1 (LRG1) was first described as a key player in pathogenic ocular neovascularization almost a decade ago. Since then, an increasing number of publications have reported the involvement of LRG1 in multiple human conditions including cancer, diabetes, cardiovascular disease, neurological disease, and inflammatory disorders. The purpose of this review is to provide, for the first time, a comprehensive overview of the LRG1 literature considering its role in health and disease. Although LRG1 is constitutively expressed by hepatocytes and neutrophils, Lrg1−/− mice show no overt phenotypic abnormality suggesting that LRG1 is essentially redundant in development and homeostasis. However, emerging data are challenging this view by suggesting a novel role for LRG1 in innate immunity and preservation of tissue integrity. While our understanding of beneficial LRG1 functions in physiology remains limited, a consistent body of evidence shows that, in response to various inflammatory stimuli, LRG1 expression is induced and directly contributes to disease pathogenesis. Its potential role as a biomarker for the diagnosis, prognosis and monitoring of multiple conditions is widely discussed while dissecting the mechanisms underlying LRG1 pathogenic functions. Emphasis is given to the role that LRG1 plays as a vasculopathic factor where it disrupts the cellular interactions normally required for the formation and maintenance of mature vessels, thereby indirectly contributing to the establishment of a highly hypoxic and immunosuppressive microenvironment. In addition, LRG1 has also been reported to affect other cell types (including epithelial, immune, mesenchymal and cancer cells) mostly by modulating the TGFβ signalling pathway in a context-dependent manner. Crucially, animal studies have shown that LRG1 inhibition, through gene deletion or a function-blocking antibody, is sufficient to attenuate disease progression. In view of this, and taking into consideration its role as an upstream modifier of TGFβ signalling, LRG1 is suggested as a potentially important therapeutic target. While further investigations are needed to fill gaps in our current understanding of LRG1 function, the studies reviewed here confirm LRG1 as a pleiotropic and pathogenic signalling molecule providing a strong rationale for its use in the clinic as a biomarker and therapeutic target.
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DOI：
10.1038/s41433-021-01807-4
发表时间：
2022-03
期刊：
Eye (London, England)
影响因子：
--
作者：
De Rossi G;Da Vitoria Lobo ME;Greenwood J;Moss SE
通讯作者：
Moss SE
影响因子：
3.7
作者：
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Gopinath SC
影响因子：
7.2
作者：
Codina, Ramil;Vanasse, Amelia;Jemmerson, Ronald
通讯作者：
Jemmerson, Ronald
影响因子：
3.8
作者：
Beck, Tim N.;Boumber, Yanis A.;Alpaugh, R. Katherine
通讯作者：
Alpaugh, R. Katherine
影响因子：
158.5
作者：
Ackermann, Maximilian;Verleden, Stijn E.;Jonigk, Danny
通讯作者：
Jonigk, Danny