Kupffer cell and recruited macrophage heterogeneity orchestrate granuloma maturation and hepatic immunity in visceral leishmaniasis
Abstract In murine models of visceral leishmaniasis (VL), the parasitization of resident Kupffer cells (resKCs) drives early Leishmania infantum growth in the liver, leading to granuloma formation and subsequent parasite control. Using the chronic VL model, we demonstrate that polyclonal resKCs redi...
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58360-x |
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| author | Gabriela Pessenda Tiago R. Ferreira Andrea Paun Juraj Kabat Eduardo P. Amaral Olena Kamenyeva Pedro Henrique Gazzinelli-Guimaraes Shehan R. Perera Sundar Ganesan Sang Hun Lee David L. Sacks |
| author_facet | Gabriela Pessenda Tiago R. Ferreira Andrea Paun Juraj Kabat Eduardo P. Amaral Olena Kamenyeva Pedro Henrique Gazzinelli-Guimaraes Shehan R. Perera Sundar Ganesan Sang Hun Lee David L. Sacks |
| author_sort | Gabriela Pessenda |
| collection | DOAJ |
| description | Abstract In murine models of visceral leishmaniasis (VL), the parasitization of resident Kupffer cells (resKCs) drives early Leishmania infantum growth in the liver, leading to granuloma formation and subsequent parasite control. Using the chronic VL model, we demonstrate that polyclonal resKCs redistributed to form granulomas outside the sinusoids, creating an open sinusoidal niche that was gradually repopulated by monocyte-derived KCs (moKCs) acquiring a tissue specific, homeostatic profile. Early-stage granulomas predominantly consisted of CLEC4F+KCs. In contrast, late-stage granulomas led to remodeling of the sinusoidal network and contained monocyte-derived macrophages (momacs) along with KCs that downregulated CLEC4F, with both populations expressing iNOS and pro-inflammatory chemokines. During late-stage infection, parasites were largely confined to CLEC4F-KCs. Reduced monocyte recruitment and increased resKCs proliferation in infected Ccr2 −/− mice impaired parasite control. These findings show that the ontogenic heterogeneity of granuloma macrophages is closely linked to granuloma maturation and the development of hepatic immunity in VL. |
| format | Article |
| id | doaj-art-decb3526be414654972ca662498d0eaa |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-decb3526be414654972ca662498d0eaa2025-08-20T03:07:43ZengNature PortfolioNature Communications2041-17232025-04-0116111410.1038/s41467-025-58360-xKupffer cell and recruited macrophage heterogeneity orchestrate granuloma maturation and hepatic immunity in visceral leishmaniasisGabriela Pessenda0Tiago R. Ferreira1Andrea Paun2Juraj Kabat3Eduardo P. Amaral4Olena Kamenyeva5Pedro Henrique Gazzinelli-Guimaraes6Shehan R. Perera7Sundar Ganesan8Sang Hun Lee9David L. Sacks10Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of HealthLaboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of HealthLaboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of HealthBiological Imaging Section, Research Technology Branch, National Institute of Allergy and Infectious Diseases, National Institutes of HealthLaboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of HealthBiological Imaging Section, Research Technology Branch, National Institute of Allergy and Infectious Diseases, National Institutes of HealthLaboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of HealthDepartment of Electrical and Computer Engineering, The Ohio State UniversityBiological Imaging Section, Research Technology Branch, National Institute of Allergy and Infectious Diseases, National Institutes of HealthLaboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of HealthLaboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of HealthAbstract In murine models of visceral leishmaniasis (VL), the parasitization of resident Kupffer cells (resKCs) drives early Leishmania infantum growth in the liver, leading to granuloma formation and subsequent parasite control. Using the chronic VL model, we demonstrate that polyclonal resKCs redistributed to form granulomas outside the sinusoids, creating an open sinusoidal niche that was gradually repopulated by monocyte-derived KCs (moKCs) acquiring a tissue specific, homeostatic profile. Early-stage granulomas predominantly consisted of CLEC4F+KCs. In contrast, late-stage granulomas led to remodeling of the sinusoidal network and contained monocyte-derived macrophages (momacs) along with KCs that downregulated CLEC4F, with both populations expressing iNOS and pro-inflammatory chemokines. During late-stage infection, parasites were largely confined to CLEC4F-KCs. Reduced monocyte recruitment and increased resKCs proliferation in infected Ccr2 −/− mice impaired parasite control. These findings show that the ontogenic heterogeneity of granuloma macrophages is closely linked to granuloma maturation and the development of hepatic immunity in VL.https://doi.org/10.1038/s41467-025-58360-x |
| spellingShingle | Gabriela Pessenda Tiago R. Ferreira Andrea Paun Juraj Kabat Eduardo P. Amaral Olena Kamenyeva Pedro Henrique Gazzinelli-Guimaraes Shehan R. Perera Sundar Ganesan Sang Hun Lee David L. Sacks Kupffer cell and recruited macrophage heterogeneity orchestrate granuloma maturation and hepatic immunity in visceral leishmaniasis Nature Communications |
| title | Kupffer cell and recruited macrophage heterogeneity orchestrate granuloma maturation and hepatic immunity in visceral leishmaniasis |
| title_full | Kupffer cell and recruited macrophage heterogeneity orchestrate granuloma maturation and hepatic immunity in visceral leishmaniasis |
| title_fullStr | Kupffer cell and recruited macrophage heterogeneity orchestrate granuloma maturation and hepatic immunity in visceral leishmaniasis |
| title_full_unstemmed | Kupffer cell and recruited macrophage heterogeneity orchestrate granuloma maturation and hepatic immunity in visceral leishmaniasis |
| title_short | Kupffer cell and recruited macrophage heterogeneity orchestrate granuloma maturation and hepatic immunity in visceral leishmaniasis |
| title_sort | kupffer cell and recruited macrophage heterogeneity orchestrate granuloma maturation and hepatic immunity in visceral leishmaniasis |
| url | https://doi.org/10.1038/s41467-025-58360-x |
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