A granulin-positive macrophage subtype in mycobacterial granulomas alleviates tissue damage by limiting excessive inflammation
Abstract
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 tnfα and il1β , 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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (19)
Geyang Luo
Center for Tuberculosis Research, Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of the Ministry of Education/National Health Commission/Chinese Academy of Medical Sciences (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Fudan University
Yanling Wen
Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology
Min Wang
Hao Wang
Division of Quantitative Sciences, Department of Oncology Johns Hopkins University School of Medicine Baltimore Maryland USA
Duoduo Li
Department of Pathology, Shanghai Public Health Clinical Center, Fudan University
Mingfeng Liao
Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology
Dong Zeng
Department of Pathology, Shanghai Public Health Clinical Center, Fudan University
Sizhu Luo
Center for Tuberculosis Research, Shanghai Public Health Clinical Center, Fudan University
Liangfei Niu
Center for Tuberculosis Research, Shanghai Public Health Clinical Center, Fudan University
Tao Sun
Peng Sun
State Key Laboratory of NBC Protection for Civilian
Liyi Qin
National Tuberculosis Clinical Lab, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute
Weimin Li
National Tuberculosis Clinical Lab, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute
Shu Song
Department of Pathology, Shanghai Public Health Clinical Center, Fudan University
Howard E. Takiff
Instituto Venezolano de Investigaciones Científicas, Centro de Microbiología y Biología Celular
Shuye Zhang
Clinical Center for BioTherapy, Zhongshan Hospital, Fudan University
Qian Gao
College of Information Science and Engineering
Zheng Zhang
Bo Yan
State Key Laboratory of Chemical Resource Engineering, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, College of Chemistry