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, Sacks David L
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Biological Imaging Section, Research Technology Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Nat Commun. 2025 Apr 1;16(1):3125. doi: 10.1038/s41467-025-58360-x.
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.
在内脏利什曼病（VL）的小鼠模型中，驻留库普弗细胞（resKCs）的寄生驱动了婴儿利什曼原虫在肝脏中的早期生长，导致肉芽肿形成及随后的寄生虫控制。利用慢性VL模型，我们证明多克隆resKCs重新分布以在肝血窦外形成肉芽肿，创造了一个开放的肝血窦生态位，该生态位逐渐被获得组织特异性稳态特征的单核细胞衍生的库普弗细胞（moKCs）重新填充。早期肉芽肿主要由CLEC4F阳性的库普弗细胞组成。相反，晚期肉芽肿导致肝血窦网络重塑，并包含单核细胞衍生的巨噬细胞（momacs）以及下调CLEC4F的库普弗细胞，这两种细胞群体均表达诱导型一氧化氮合酶（iNOS）和促炎趋化因子。在晚期感染期间，寄生虫主要局限于CLEC4F阳性的库普弗细胞。感染的Ccr2小鼠中单核细胞募集减少和resKCs增殖增加损害了寄生虫控制。这些发现表明肉芽肿巨噬细胞的个体发生异质性与肉芽肿成熟以及VL中肝脏免疫的发展密切相关。
