Single-cell transcriptomic profiling reveals a novel signature of necrotizing granulomatous lesions in the lungs of Mycobacterium tuberculosis-infected C3HeB/FeJ mice
Tuberculosis (TB) pathology involves complex immune responses within granulomatous lesions. Using single-cell RNA sequencing, we characterized the cellular compositions of necrotizing granulomatous lesions that developed in the lungs of Mycobacterium tuberculosis-infected C3HeB/FeJ mice. We identifi...
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Frontiers Media S.A.
2025-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1624072/full |
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| author | Shintaro Seto Shiho Omori Hajime Nakamura Hajime Nakamura Minako Hijikata Naoto Keicho Naoto Keicho |
| author_facet | Shintaro Seto Shiho Omori Hajime Nakamura Hajime Nakamura Minako Hijikata Naoto Keicho Naoto Keicho |
| author_sort | Shintaro Seto |
| collection | DOAJ |
| description | Tuberculosis (TB) pathology involves complex immune responses within granulomatous lesions. Using single-cell RNA sequencing, we characterized the cellular compositions of necrotizing granulomatous lesions that developed in the lungs of Mycobacterium tuberculosis-infected C3HeB/FeJ mice. We identified 11 distinct major cell types, including phagocytes such as neutrophils and macrophages, and T cells, natural killer cells, B cells, dendritic cells, and plasmacytoid dendritic cells. Among T cells, particularly, Pdcd1+ γδ T cells were detected in necrotizing granulomatous lesions, suggesting their potential role in the pathogenicity of M. tuberculosis. Within the macrophage populations, we identified a cluster with significantly higher Plin2 expression compared to other clusters, whose transcriptomic profile was consistent with that of foamy macrophages. A subset of the Plin2-expressing macrophages was identified as a major source of Ifnb1 and Cxcl1, suggesting their involvement in type I interferon signaling and neutrophil recruitment. Furthermore, we identified Flrt2, Hyal1, and Mmp13 as novel molecular markers of Plin2-expressing macrophages, which were localized to the peripheral rim regions of necrotizing granulomas. In conclusion, our results provide the immune landscape of necrotizing granulomas and reveal novel functional states of macrophages contributing to TB pathogenesis. |
| format | Article |
| id | doaj-art-d67ff433f72b4974a36b7ed07e7d464d |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-d67ff433f72b4974a36b7ed07e7d464d2025-08-20T03:44:35ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-08-011610.3389/fimmu.2025.16240721624072Single-cell transcriptomic profiling reveals a novel signature of necrotizing granulomatous lesions in the lungs of Mycobacterium tuberculosis-infected C3HeB/FeJ miceShintaro Seto0Shiho Omori1Hajime Nakamura2Hajime Nakamura3Minako Hijikata4Naoto Keicho5Naoto Keicho6Department of Pathophysiology and Host Defense, The Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, Tokyo, JapanDepartment of Pathophysiology and Host Defense, The Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, Tokyo, JapanDepartment of Pathophysiology and Host Defense, The Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, Tokyo, JapanDepartment of Basic Mycobacteriosis, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, JapanDepartment of Pathophysiology and Host Defense, The Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, Tokyo, JapanDepartment of Basic Mycobacteriosis, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, JapanThe Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, Tokyo, JapanTuberculosis (TB) pathology involves complex immune responses within granulomatous lesions. Using single-cell RNA sequencing, we characterized the cellular compositions of necrotizing granulomatous lesions that developed in the lungs of Mycobacterium tuberculosis-infected C3HeB/FeJ mice. We identified 11 distinct major cell types, including phagocytes such as neutrophils and macrophages, and T cells, natural killer cells, B cells, dendritic cells, and plasmacytoid dendritic cells. Among T cells, particularly, Pdcd1+ γδ T cells were detected in necrotizing granulomatous lesions, suggesting their potential role in the pathogenicity of M. tuberculosis. Within the macrophage populations, we identified a cluster with significantly higher Plin2 expression compared to other clusters, whose transcriptomic profile was consistent with that of foamy macrophages. A subset of the Plin2-expressing macrophages was identified as a major source of Ifnb1 and Cxcl1, suggesting their involvement in type I interferon signaling and neutrophil recruitment. Furthermore, we identified Flrt2, Hyal1, and Mmp13 as novel molecular markers of Plin2-expressing macrophages, which were localized to the peripheral rim regions of necrotizing granulomas. In conclusion, our results provide the immune landscape of necrotizing granulomas and reveal novel functional states of macrophages contributing to TB pathogenesis.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1624072/fulltuberculosisMycobacterium tuberculosisC3HeB/FeJ TB modelnecrotizing granulomafoamy macrophagescRNA-seq |
| spellingShingle | Shintaro Seto Shiho Omori Hajime Nakamura Hajime Nakamura Minako Hijikata Naoto Keicho Naoto Keicho Single-cell transcriptomic profiling reveals a novel signature of necrotizing granulomatous lesions in the lungs of Mycobacterium tuberculosis-infected C3HeB/FeJ mice Frontiers in Immunology tuberculosis Mycobacterium tuberculosis C3HeB/FeJ TB model necrotizing granuloma foamy macrophage scRNA-seq |
| title | Single-cell transcriptomic profiling reveals a novel signature of necrotizing granulomatous lesions in the lungs of Mycobacterium tuberculosis-infected C3HeB/FeJ mice |
| title_full | Single-cell transcriptomic profiling reveals a novel signature of necrotizing granulomatous lesions in the lungs of Mycobacterium tuberculosis-infected C3HeB/FeJ mice |
| title_fullStr | Single-cell transcriptomic profiling reveals a novel signature of necrotizing granulomatous lesions in the lungs of Mycobacterium tuberculosis-infected C3HeB/FeJ mice |
| title_full_unstemmed | Single-cell transcriptomic profiling reveals a novel signature of necrotizing granulomatous lesions in the lungs of Mycobacterium tuberculosis-infected C3HeB/FeJ mice |
| title_short | Single-cell transcriptomic profiling reveals a novel signature of necrotizing granulomatous lesions in the lungs of Mycobacterium tuberculosis-infected C3HeB/FeJ mice |
| title_sort | single cell transcriptomic profiling reveals a novel signature of necrotizing granulomatous lesions in the lungs of mycobacterium tuberculosis infected c3heb fej mice |
| topic | tuberculosis Mycobacterium tuberculosis C3HeB/FeJ TB model necrotizing granuloma foamy macrophage scRNA-seq |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1624072/full |
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