单核细胞/巨噬细胞来源的白细胞介素-15介导1型糖尿病CD226+ B细胞的促炎表型。

IF 10.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Jingyue Li, Xin Liang, Mingjiu Zhao, Wenjun Luo, Juan Huang, Yang Xiao, Jiaqi Huang, Bin Zhao, Zhiguang Zhou
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引用次数: 0

摘要

背景:1型糖尿病(T1D)以自身免疫介导的胰腺β细胞破坏为特征。虽然传统上被认为是一种由T细胞主导的疾病,但最近的研究强调了B细胞在T1D发展中的关键作用。全基因组关联研究(GWAS)显示CD226与几种自身免疫性疾病的易感性相关,包括T1D。我们最近的工作确定了CD226+ CD8+ T细胞在T1D中的致病作用。然而,CD226+ B细胞在T1D发展中的参与尚不清楚。方法:采用流式细胞术检测CD226+ B细胞在T1D患者和非肥胖型糖尿病(NOD)小鼠中的表达及功能特征。通过RNA测序和分子生物学实验揭示其调控机制。此外,还进行了体内干预,以探索T1D的潜在预防和治疗靶点。结果:T1D患者CD226+ B细胞百分比增加,且与疾病严重程度呈正相关。T1D患者和NOD小鼠的CD226+ B细胞表现出激活、增殖和产生促炎细胞因子的能力增强,同时糖酵解代谢增强。机制研究表明,单核细胞或巨噬细胞分泌的白细胞介素-15 (IL-15)可促进CD226+ B细胞的炎症反应。重要的是,使用抗cd132单克隆抗体(anti-CD132)或抗IL-15单克隆抗体(anti-IL-15),阻断IL-15信号传导,有效地预防了T1D的发病。此外,抗cd3单克隆抗体(抗cd3)和抗cd132联合治疗可协同逆转环磷酰胺加速NOD小鼠的高血糖。我们的研究证明了单核细胞/巨噬细胞- il -15- cd226 + B细胞轴在T1D免疫发病机制中的新作用,并为T1D免疫治疗提供了潜在的靶点。基金资助:非传染性慢性病国家科技重大专项(2023ZD0507300、2023ZD0507303、2023ZD0508200、2023ZD0508201),国家自然科学基金项目(82570973、82170795、82470814、82100949、82470931),福荣实验室科研计划项目(2024PT5105),中南大学跨学科高级研究计划项目(2023QYJC008)。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Monocyte/macrophage-derived interleukin-15 mediates the pro-inflammatory phenotype of CD226+ B cells in type 1 diabetes.

Background: Type 1 diabetes (T1D) is characterised by the autoimmune-mediated destruction of pancreatic β-cells. Although traditionally viewed as a disease dominated by T cells, recent studies have emphasised the crucial role of B cells in the development of T1D. Genome-wide association studies (GWAS) have revealed that CD226 is related to susceptibility to several autoimmune diseases, including T1D. Our recent work identified a pathogenic role of CD226+ CD8+ T cells in T1D. However, the involvement of CD226+ B cells in T1D development remains unclear.

Methods: The expression and functional characteristics of CD226+ B cells in T1D patients and non-obese diabetic (NOD) mice were detected by flow cytometry. RNA sequencing and molecular biology experiments were performed to reveal regulatory mechanisms. In addition, in vivo interventions were conducted to explore potential preventive and therapeutic targets for T1D.

Findings: The percentage of CD226+ B cells is increased and positively correlated with disease severity in T1D. CD226+ B cells from T1D patients and NOD mice exhibit increased capability for activation, proliferation, and production of pro-inflammatory cytokines along with heightened glycolytic metabolism. Mechanistic studies have revealed that interleukin-15 (IL-15) secreted by monocytes or macrophages promotes the inflammatory response of CD226+ B cells. Importantly, the use of an anti-CD132 monoclonal antibody (anti-CD132) or an anti-IL-15 monoclonal antibody (anti-IL-15), which blocks IL-15 signalling, effectively prevented the disease onset of T1D. Furthermore, combination therapy with anti-CD3 monoclonal antibody (anti-CD3) and anti-CD132 synergistically reversed hyperglycemia in cyclophosphamide-accelerated NOD mice.

Interpretation: Our study demonstrates a novel role of the monocyte/macrophage-IL-15-CD226+ B cell axis in T1D immunopathogenesis and provides potential targets for T1D immunotherapy.

Funding: This work was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0507300, 2023ZD0507303, 2023ZD0508200, and 2023ZD0508201), the Natural Science Foundation of China (82570973, 82170795, 82470814, 82100949, and 82470931), the Scientific Research Program of FuRong Laboratory (2024PT5105) and the Central South University Research Programme of Advanced Interdisciplinary Studies (2023QYJC008).

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来源期刊
EBioMedicine
EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
17.70
自引率
0.90%
发文量
579
审稿时长
5 weeks
期刊介绍: eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.
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