Monocyte–macrophage dynamics as key in disparate lung and peripheral immune responses in severe anti‐melanoma differentiation‐associated gene 5‐positive dermatomyositis‐related interstitial lung disease

作者：Jia Shi, Xiaoya Pei, Jinmin Peng, Chanyuan Wu, Yunpeng Lv, Xiaoman Wang, Yangzhong Zhou, Xueting Yuan, Xingbei Dong, Shuang Zhou, Xu D, Jiuliang Zhao, Jun Liu, Jiao Huang, Bin Du, Chen Yao, Xiaofeng Zeng, Mengtao Li, Hou‐Zao Chen, Qian Wang · 发表于：Clinical and Translational Medicine · 年份：2025 · DOI：10.1002/ctm2.70226 · 被引用次数：13 · 研究领域：Inflammatory Myopathies and Dermatomyositis、Systemic Sclerosis and Related Diseases、Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis

BACKGROUND: Anti-melanoma differentiation-associated gene 5-positive dermatomyositis (anti-MDA5+ DM) is a rare inflammatory autoimmune disorder often complicated by life-threatening rapidly progressive interstitial lung disease (RP-ILD). The underlying mechanisms driving immune dysfunction and lung injury, however, remain poorly understood. The study aims to gain insights into the disrupted immune landscape in peripheral and pulmonary compartments of severe anti-MDA5+ DM and explore potential therapeutic targets. METHODS: We employed single-cell RNA sequencing to examine cellular constituents within five patients' bronchoalveolar lavage fluid and paired peripheral blood mononuclear cells. Luminex assay and flow cytometry were further applied to validate the results. RESULTS: Our analysis revealed starkly contrasting immune landscapes between the periphery and lungs, with peripheral immune suppression juxtaposed against pulmonary immune hyperactivation. Central to this dysregulation was the monocyte-macrophage lineage. Circulating monocytes exhibited an immunosuppressive phenotype, characterised by diminished cytokine production, reduced MHC II expression, and features resembling myeloid-derived suppressor cells. These monocytes were recruited to the lungs, where they differentiated into monocyte-derived alveolar macrophages (Mo-AMs) with robust proinflammatory and profibrotic activities. Mo-AMs drove cytokine storms and produced chemokines that amplified inflammatory cell rec...