LRG1：疾病发病机制中的新兴参与者,Journal of Biomedical Science

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LRG1：疾病发病机制中的新兴参与者
Journal of Biomedical Science ( IF 9.0 ) Pub Date : 2022-01-21 , DOI: 10.1186/s12929-022-00790-6
Carlotta Camilli ₁ , Alexandra E Hoeh ₁ , Giulia De Rossi ₁ , Stephen E Moss ₁ , John Greenwood ₁

Affiliation

大约十年前，分泌性富含亮氨酸的 α-2 糖蛋白 1 (LRG1) 首次被描述为致病性眼部新生血管形成的关键参与者。从那时起，越来越多的出版物报道了 LRG1 与多种人类疾病有关，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对 LRG1 文献进行全面概述，考虑其在健康和疾病中的作用。尽管LRG1由肝细胞和中性粒细胞组成型表达，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本质上是多余的。然而，新出现的数据表明 LRG1 在先天免疫和保护组织完整性方面具有新的作用，从而挑战了这一观点。虽然我们对 LRG1 在生理学中有益功能的了解仍然有限，但一致的证据表明，响应各种炎症刺激，LRG1 表达被诱导并直接促进疾病发病机制。在剖析 LRG1 致病功能的机制时，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得到了广泛讨论。重点强调了 LRG1 作为血管病变因子的作用，它破坏成熟血管形成和维持通常所需的细胞相互作用，从而间接促进高度缺氧和免疫抑制微环境的建立。此外，据报道，LRG1 主要通过以上下文依赖性方式调节 TGFβ 信号通路来影响其他细胞类型（包括上皮细胞、免疫细胞、间充质细胞和癌细胞）。至关重要的是，动物研究表明，通过基因删除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 TGFβ 信号传导上游调节剂的作用，LRG1 被建议作为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 功能理解的空白，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的使用提供了强有力的理由。

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LRG1: an emerging player in disease pathogenesis

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.

更新日期：2022-01-23

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