IL7R+ T细胞-巨噬细胞串扰将哮喘与阿尔茨海默病的发病机制联系起来：整合孟德尔随机化和细胞聊天分析

IF 2.7 3区心理学 Q2 BEHAVIORAL SCIENCES

Brain and Behavior Pub Date : 2025-09-15 DOI:10.1002/brb3.70809

Jing Yang, Zixing Liu, Xiaofang Li, Yichong Qiu, Qiong Liu, Xiufang Huang, Leshen Lian

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引用次数: 0

摘要

目的流行病学调查显示，重度哮喘患者阿尔茨海默病（AD）发病率较高。然而，这种关系的因果关系仍然不确定。目前的研究旨在使用孟德尔随机化（MR）分析来检查遗传预测的中度至重度哮喘与AD风险之间的潜在联系。方法利用欧洲血统个体AD （n = 455,258）和中重度哮喘（n = 57,695）全基因组关联研究的汇总统计数据进行MR研究。还进行了SMR分析，以研究这些基因的表达是否与AD或中重度哮喘结局相关，以检测中重度哮喘与AD之间的因果关系。使用连锁不平衡评分回归（LDSC）估计中度至重度哮喘与AD之间的全基因组遗传相关性。获得哮喘相关外周血单核细胞（PBMC）数据和AD脑脊液（CSF）的单细胞RNA测序（scRNA-seq）数据集，进一步研究哮喘与AD不同生物学通路之间的串扰。结果在多变量MR分析中，控制混杂危险因素后，中度至重度哮喘对AD风险的影响持续存在（ORIVW = 1.01, 95% CI = 1.00-1.02, p = 3.85 × 10−3）。此外，研究表明1.8%的总效应（中度至重度哮喘）是由嗜酸性粒细胞介导的。SMR分析和全基因MR分析揭示了许多与AD和中度至重度哮喘易感性相关的基因靶点。在这些靶点中，FPR1（甲酰基肽受体1）、IL1RAP（白细胞介素1受体辅助蛋白）、IL7R（白细胞介素7受体）和IL18RAP（白细胞介素18受体辅助蛋白）作为AD和中重度哮喘的潜在治疗靶点值得进一步探索。LDSC分析显示哮喘和AD之间无显著重叠（rg = 0.0436, SE = 0.0813, p = 0.592），提示不同的遗传结构。哮喘PBMCs和AD CSF的单细胞RNA测序分析显示，IL7R可能利用MIF-CD74-CXCR4通路完成CD4 T细胞和巨噬细胞之间的串音，并参与AD疾病的发展。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

IL7R+ T Cell-Macrophage Crosstalk Links Asthma to Alzheimer's Pathogenesis: Integrating Mendelian Randomization and CellChat Analysis

查看原文本刊更多论文

IL7R+ T Cell-Macrophage Crosstalk Links Asthma to Alzheimer's Pathogenesis: Integrating Mendelian Randomization and CellChat Analysis

Purpose

Epidemiological investigation has revealed a higher incidence of Alzheimer's disease (AD) in individuals with severe asthma. However, the causality of this relationship remains uncertain. The current research aimed to examine the potential link between genetically predicted moderate to severe asthma and the risk of AD using Mendelian randomization (MR) analysis.

Methods

Summary statistics obtained from genome-wide association studies of AD (n = 455,258) and moderate to severe asthma (n = 57,695) in individuals of European ancestry were utilized in this MR study. SMR analysis was also performed to investigate whether the expression of these genes was correlated with AD or moderate to severe asthma outcomes to detect a causal relationship between moderate to severe asthma and AD. Genome-wide genetic correlation between moderate to severe asthma and AD was estimated using linkage disequilibrium score regression (LDSC). Single-cell RNA sequencing (scRNA-seq) datasets of asthma-related peripheral blood mononuclear cell (PBMC) data and AD cerebrospinal fluid (CSF) were obtained to further investigate the crosstalk between the different biological pathways in asthma and AD.

Results

The impact of moderate to severe asthma on AD risk persisted (OR_IVW= 1.01, 95% CI = 1.00–1.02, p = 3.85 × 10⁻³) after controlling for confounder risk factors in multivariable MR analyses. Additionally, the study showed that 1.8% of the total effect (moderate to severe asthma) was mediated by eosinophils. SMR analysis and the gene-wide MR analysis revealed numerous gene targets linked to the susceptibility of AD and moderate to severe asthma. Among these targets, FPR1 (Formyl Peptide Receptor 1), IL1RAP (Interleukin 1 Receptor Accessory Protein), IL7R (Interleukin 7 Receptor), and IL18RAP (Interleukin 18 Receptor Accessory Protein) warrant additional exploration as potential therapeutic targets for AD and moderate to severe asthma. LDSC analysis revealed no significant overlap between asthma and AD (rg = 0.0436, SE = 0.0813, p = 0.592), suggesting distinct genetic architectures. Integrated single-cell RNA sequencing analysis of asthma PBMCs and AD CSF revealed IL7R may utilize the MIF-CD74-CXCR4 pathway to complete crosstalk between CD4 T cells and macrophages and contribute to AD disease development.

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来源期刊

Brain and Behavior BEHAVIORAL SCIENCES-NEUROSCIENCES

CiteScore

5.30

自引率

0.00%

发文量

352

审稿时长

14 weeks

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