12-脂氧合酶抑制剂可延长人类基因替代小鼠自身免疫性糖尿病的发病时间。

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Titli Nargis, Charanya Muralidharan, Jacob R Enriquez, Jiayi E Wang, Kerim B Kaylan, Advaita Chakraborty, Sarida Pratuangtham, Kayla Figatner, Jennifer B Nelson, Sarah C May, Jerry L Nadler, Matthew B Boxer, David J Maloney, Sarah A Tersey, Raghavendra G Mirmira
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引用次数: 0

摘要

1型糖尿病(T1D)的特点是产生胰岛素的β细胞遭到自身免疫性破坏,这涉及β细胞与先天性和适应性免疫系统细胞之间的相互作用。我们使用一种小鼠模型研究了靶向 12-脂氧合酶(12-LOX)的治疗潜力,这种酶与β细胞和巨噬细胞的炎症通路有牵连。我们的研究结果表明,VLX-1005(一种强效的 12-LOX 抑制剂)能有效延缓人类基因替代非肥胖糖尿病小鼠自身免疫性糖尿病的发病。通过空间蛋白质组学分析,VLX-1005 治疗导致浸润的 T 细胞、B 细胞和巨噬细胞明显减少,免疫检查点分子 PD-L1 也随之增加,这表明免疫抑制微环境发生了转变。对分离的胰岛和极化的促炎巨噬细胞进行的RNA测序分析表明,VLX-1005治疗后,细胞因子反应途径发生了显著改变,干扰素反应也有所降低。我们的研究表明,ALOX12 人类替代基因小鼠为 LOX 抑制剂的临床前评估提供了一个平台,并支持 VLX-1005 作为人类 12-LOX 的抑制剂,这种抑制剂能与酶靶点结合,改变胰岛和巨噬细胞的炎症表型,从而促进自身免疫性糖尿病的延缓。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
12-Lipoxygenase inhibition delays onset of autoimmune diabetes in human gene replacement mice.

Type 1 diabetes (T1D) is characterized by the autoimmune destruction of insulin-producing β cells and involves an interplay between β cells and cells of the innate and adaptive immune systems. We investigated the therapeutic potential of targeting 12-lipoxygenase (12-LOX), an enzyme implicated in inflammatory pathways in β cells and macrophages, using a mouse model in which the endogenous mouse Alox15 gene is replaced by the human ALOX12 gene. Our finding demonstrated that VLX-1005, a potent 12-LOX inhibitor, effectively delayed the onset of autoimmune diabetes in human gene replacement non-obese diabetic mice. By spatial proteomics analysis, VLX-1005 treatment resulted in marked reductions in infiltrating T and B cells and macrophages, with accompanying increases in immune checkpoint molecule PD-L1, suggesting a shift toward an immunosuppressive microenvironment. RNA sequencing analysis of isolated islets and polarized proinflammatory macrophages revealed significant alteration of cytokine-responsive pathways and a reduction in IFN response after VLX-1005 treatment. Our studies demonstrated that the ALOX12 human replacement gene mouse provides a platform for the preclinical evaluation of LOX inhibitors and supports VLX-1005 as an inhibitor of human 12-LOX that engages the enzymatic target and alters the inflammatory phenotypes of islets and macrophages to promote the delay of autoimmune diabetes.

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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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