Kupffer cells heterogeneity and replacement by monocyte-derived KCs contributes to visceral leishmaniasis resistance

Abstract

Abstract Visceral leishmaniasis (VL) is a potentially fatal disease transmitted by sand fly bites and caused by Leishmania (L. donovani/L. infantum) protozoa. Kupffer cells (KCs) are the liver embryonic resident macrophages (emKCs), characterized by Clec4f and Tim4 expression and their sessile behavior within the liver sinusoids. KCs maintain their numbers via self-proliferation during homeostasis but can be replaced by monocyte-derived cells (moKCs) during inflammation. In the murine VL model, KCs are important for both initial parasite growth and granuloma formation, the latter being associated with the eventual protective response. The objective of our study is to investigate KC proliferation, migration, death, and their replacement by moKCs in VL. We found that KC proliferation was enhanced at 19 d.p.i., while at 42 d.p.i. the granulomas cores contained mixed KC clonal lineages and were located outside the liver sinusoids. At the same time point, Clec4f and Tim4 expression was reduced, and we found evidence of KC apoptosis and ferroptosis. Parabiotic mice demonstrated KC populations that bore either congenic marker, and CCR2 −/−infected mice showed enhanced frequencies of emKCs, reduced frequencies of moKCs, and higher parasite loads compared to WT mice. Reduction of ferroptosis in BACH1 −/−mice resulted in lower frequencies of moKCs. Collectively, our data indicates that KCs migrate to the liver parenchyma to form granulomas, facilitating their activation by other immune cells, and that KC death results in their partial replacement by moKCs, contributing to increased parasite killing. Thus, KC heterogeneity is an important hallmark of hepatic resistance in VL. Funded by the Division of Intramural Research, NIAID.