A granulin-positive macrophage subtype in mycobacterial granulomas alleviates tissue damage by limiting excessive inflammation

• 成果类型: Article
• 署名作者: Luo, Geyang; Wen, Yanling; Wang, Min; Wang, Hao; Li, Duoduo; Liao, Mingfeng; Zeng, Dong; Luo, Sizhu; Niu, Liangfei; Sun, Tao; Sun, Peng; Qin, Liyi; Li, Weimin; Song, Shu; Takiff, Howard E.; Zhang, Shuye; Gao, Qian; Zhang, Zheng; Yan, Bo
• 署名单位: Fudan University; Southern University of Science & Technology; Fudan University; Fudan University; Capital Medical University; Venezuelan Institute Science Research; Fudan University; The Third People's Hospital of Shenzhen
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8935
• DOI: 10.1073/pnas.2413946122
• 发表日期: 2025-08-05
• 关键词: tumor-necrosis-factor; fluorescent proteins; mediates resistance; immune-response; rna-seq; tuberculosis; progranulin; zebrafish; gene; marinum

摘要

Granulomas play a crucial role in the pathology of tuberculosis, but the immune environment governing their formation remains largely unknown. To explore the dynamic changes in the immune microenvironment during the formation of tuberculous granulomas, we infected adult zebrafish with Mycobacterium marinum and then examined uninfected and infected kidneys, as well as large and small granulomas in the kidneys. Using single-cell RNA sequencing technology, we identified two major macrophage subpopulations in the hematopoietic tissue (kidney) of zebrafish under uninfected physiological conditions: monocyte derived and tissue-resident macrophages. Interestingly, the infection induced the emergence of epithelioid cells and a previously undescribed grna.2+ macrophage subpopulation. Depletion of grna.2+ macrophages with the nitroreductase-metronidazole ablation system resulted in shortened zebrafish survival after infection, increased bacterial load, and more granulomas, especially necrotic granulomas. Depletion of grna.2+ macrophages also produced a denser granuloma structure with fewer T cells. RNA-seq and flow cytometry analysis revealed that depletion of grna.2+ macrophages led to upregulated inflammatory signaling pathways, including tnf alpha and il1 beta, and increased macrophage lytic cell death. Similarly, in samples from tuberculosis patients, we also identified GRN-positive macrophages, which exhibit similar anti-inflammatory functions. This subset of grna.2+ macrophages present in developing granulomas can suppress excessive inflammatory responses to alleviate macrophage lytic death, reduce tissue damage, promote T cell infiltration and ultimately help control mycobacterial growth in vivo.