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Although mechanistic target of rapamycin complex 1 (mTORC1) activation in macrophages drives granuloma development in sarcoidosis by enhancing macrophage proliferation, little is known about the macrophage subsets that proliferate and mature into granuloma macrophages. Here, we show that aberrantly increased monocytopoiesis gives rise to granulomas in a sarcoidosis model, in which Tsc2, a negative regulator of mTORC1, is conditionally deleted in CSF1R-expressing macrophages (Tsc2csf1r\u0394 mice). In Tsc2csf1r\u0394 mice, common myeloid progenitors (CMPs), granulocyte-monocyte progenitors (GMPs), common monocyte progenitors \/ monocyte progenitors (cMoPs \/ MPs), inducible monocyte progenitors (iMoPs), and Ly6Cint CX3CR1low CD14\u2212 immature monocytes (iMOs), but not monocyte-dendritic cell progenitors (MDPs) and common dendritic cell progenitors (CDPs), accumulated and proliferated in the spleen. Consistent with this, monocytes, neutrophils, and neutrophil-like monocytes increased in the spleens of Tsc2csf1r\u0394 mice, whereas dendritic cells did not. The adoptive transfer of splenic iMOs into wild-type mice gave rise to granulomas in the liver and lungs. In these target organs, iMOs matured into Ly6Chi classical monocytes\/macrophages (cMOs). Giant macrophages (gMAs) also accumulated in the liver and lungs, which were similar to granuloma macrophages in expression of cell surface markers such as MerTK and SLAMF7. Furthermore, the gMA-specific genes were expressed in human macrophages from sarcoidosis skin lesions. These results suggest that mTORC1 drives granuloma development by promoting the proliferation of monocyte\/neutrophil progenitors and iMOs predominantly in the spleen, and that proliferating iMOs mature into cMOs and then gMAs to give rise to granuloma after migration into the liver and lungs in sarcoidosis.<\/jats:p>","DOI":"10.1093\/intimm\/dxad054","type":"journal-article","created":{"date-parts":[[2023,12,26]],"date-time":"2023-12-26T19:18:23Z","timestamp":1703618303000},"page":"183-196","source":"Crossref","is-referenced-by-count":9,"title":["Aberrant monocytopoiesis drives granuloma development in sarcoidosis"],"prefix":"10.1093","volume":"36","author":[{"given":"Ryosuke","family":"Hiranuma","sequence":"first","affiliation":[{"name":"Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo , Tokyo , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryota","family":"Sato","sequence":"additional","affiliation":[{"name":"Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo , Tokyo , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiyoshi","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo , Tokyo , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9332-0369","authenticated-orcid":false,"given":"Satoshi","family":"Nakamizo","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Kyoto University Graduate School of Medicine , Kyoto , Japan"},{"name":"Alliance Laboratory for Advanced Medical Research, Kyoto University Graduate School of Medicine , Kyoto , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Asano","sequence":"additional","affiliation":[{"name":"Laboratory of Immune Regulation, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences , Tokyo 192-0392 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuma","family":"Shibata","sequence":"additional","affiliation":[{"name":"Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo , Tokyo , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryutaro","family":"Fukui","sequence":"additional","affiliation":[{"name":"Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo , Tokyo , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoichi","family":"Furukawa","sequence":"additional","affiliation":[{"name":"Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo , Tokyo , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0773-0554","authenticated-orcid":false,"given":"Kenji","family":"Kabashima","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Kyoto University Graduate School of Medicine , Kyoto , Japan"},{"name":"Skin Research Institute of Singapore (SRIS) and A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR) , 8A Biomedical Grove, IMMUNOS Building, Biopolis , Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kensuke","family":"Miyake","sequence":"additional","affiliation":[{"name":"Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo , Tokyo , 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