Kupffer cell and recruited macrophage heterogeneity orchestrate granuloma maturation and hepatic immunity in visceral leishmaniasis

Authors

Gabriela Pessenda, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Tiago R. Ferreira, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Andrea Paun, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Juraj Kabat, Biological Imaging Section, Research Technology Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Eduardo P. Amaral, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Olena Kamenyeva, Biological Imaging Section, Research Technology Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Pedro Henrique Gazzinelli-Guimaraes, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Shehan R. Perera, Department of Electrical and Computer Engineering, The Ohio State University, Columbus, OH, USA.
Sundar Ganesan, Biological Imaging Section, Research Technology Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Sang Hun Lee, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
David L. Sacks, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. dsacks@niaid.nih.gov.

Document Type

Journal Article

Publication Date

4-1-2025

Journal

Nature communications

Volume

16

Issue

1

DOI

10.1038/s41467-025-58360-x

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 CLEC4FKCs. 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 CLEC4FKCs. 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.

APA Citation

Pessenda, Gabriela; Ferreira, Tiago R.; Paun, Andrea; Kabat, Juraj; Amaral, Eduardo P.; Kamenyeva, Olena; Gazzinelli-Guimaraes, Pedro Henrique; Perera, Shehan R.; Ganesan, Sundar; Lee, Sang Hun; and Sacks, David L., "Kupffer cell and recruited macrophage heterogeneity orchestrate granuloma maturation and hepatic immunity in visceral leishmaniasis" (2025). GW Authored Works. Paper 7128.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/7128

Department

Microbiology, Immunology, and Tropical Medicine