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<p>Chronic obstructive pulmonary disease (COPD) is a leading global cause of mortality, with alveolar macrophages (AMs) dysfunction implicated in pathogenesis, though key molecular drivers remain unclear. This study integrated multi-omics approaches to identify causal AMs-derived factors in COPD. Single-cell RNA sequencing (scRNA-seq) of human lung tissues revealed a significantly increased proportion of macrophages, particularly enriched AMs clusters (0, 1, 5), in COPD patients versus controls. Two-sample Mendelian randomization (MR) analysis of 1,283 AMs-specific genes identified CXCL16 as having a robust negative causal relationship with COPD risk across European (IVW OR = 0.944, <i>P</i> = 0.039) and East Asian (Weighted median OR = 0.858, <i>P</i> = 0.008) populations. Bulk RNA-seq confirmed decreased CXCL16 expression in COPD lungs. Cell-cell chat analysis indicated that CXCL16 + AMs mediated critical immune interactions via pathways like MIF-CD74/CD44. Critically, CXCL16 deficiency in AMs drives COPD progression by disrupting immune-metabolic homeostasis. These findings establish CXCL16 downregulation in AMs as a novel causal mechanism in COPD and highlight its potential as a therapeutic target for restoring macrophage function and halting disease advancement.</p>

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Impaired immune metabolism in COPD driven by dysfunction of CXCL16 + alveolar macrophages: multivariate causal evidence

  • 期刊论文

  • 发表日期：

    2025年9月30日

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  • Xianqiang Zhou,
  • Yixin Zhang,
  • Jie Yang,
  • Zhengjie Jin,
  • Zhancheng Gao,
  • Cuiling Feng

摘要

Chronic obstructive pulmonary disease (COPD) is a leading global cause of mortality, with alveolar macrophages (AMs) dysfunction implicated in pathogenesis, though key molecular drivers remain unclear. This study integrated multi-omics approaches to identify causal AMs-derived factors in COPD. Single-cell RNA sequencing (scRNA-seq) of human lung tissues revealed a significantly increased proportion of macrophages, particularly enriched AMs clusters (0, 1, 5), in COPD patients versus controls. Two-sample Mendelian randomization (MR) analysis of 1,283 AMs-specific genes identified CXCL16 as having a robust negative causal relationship with COPD risk across European (IVW OR = 0.944, P = 0.039) and East Asian (Weighted median OR = 0.858, P = 0.008) populations. Bulk RNA-seq confirmed decreased CXCL16 expression in COPD lungs. Cell-cell chat analysis indicated that CXCL16 + AMs mediated critical immune interactions via pathways like MIF-CD74/CD44. Critically, CXCL16 deficiency in AMs drives COPD progression by disrupting immune-metabolic homeostasis. These findings establish CXCL16 downregulation in AMs as a novel causal mechanism in COPD and highlight its potential as a therapeutic target for restoring macrophage function and halting disease advancement.