自身免疫性糖尿病
糖尿病
脂氧合酶
医学
基因
内分泌学
内科学
药理学
免疫学
化学
1型糖尿病
生物化学
酶
作者
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
出处
期刊:JCI insight
[American Society for Clinical Investigation]
日期:2024-11-12
标识
DOI:10.1172/jci.insight.185299
摘要
Type 1 diabetes (T1D) is characterized by the autoimmune destruction of insulin-producing beta cells and involves an interplay between beta 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 beta 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 towards an immune-suppressive microenvironment. RNA sequencing analysis of isolated islets and polarized proinflammatory macrophages revealed significant alteration of cytokine-responsive pathways and a reduction in interferon 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.
科研通智能强力驱动
Strongly Powered by AbleSci AI