Kupffer cell replacement by monocyte-derived cells and granuloma heterogeneity improve visceral leishmaniasis control
Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B563
Abstract ID: 4528
Presenting Author:
Gabriela Pessenda , Postdoctoral fellow at NIAID, NIH
Abstract:
Kupffer cells (resKCs) are liver resident macrophages that can be replaced by monocyte-derived KCs (moKCs) under inflammatory conditions. KC replacement in the context of chronic infections has been little studied. Granuloma formation during chronic visceral leishmaniasis (VL) is initiated by KCs and associated with better disease outcomes. We sought to investigate KC replacement and granuloma composition during VL. At 42 d.p.i., KCs were heterogeneous and comprised of 4 subsets based on Clec4f and Tim4 expression. Parabiosis and absence of monocyte infiltration in infected Ccr2-/- mice showed that Tim4+ cells were resKCs, while Tim4- cells were of monocytic origin. We found evidence of ferroptosis in KCs from infected mice, and reduced ferroptosis in infected Bach1-/- mice resulted in lower frequency of moKCs and monocyte-derived cells (mocells). ResKCs also migrated outside of the sinusoids to form granuloma cores. Single-cell RNA sequencing showed that resKCs maintained their anti-inflammatory program during infection, but mocells and early differentiated moKCs were pro-inflammatory. Ccr2-/- mice showed more parasites in the liver compared to WT mice at 42 d.p.i., while repopulating the KC niche with moKCs resulted in lower parasite loads. We demonstrated that ferroptotic KC death and migration outside of the sinusoids contributed to an open KC niche and replacement by moKCs. Mocells and early differentiated moKCs were pro-inflammatory and favored parasite control.
Kupffer cell replacement by monocyte-derived cells and granuloma heterogeneity improve visceral leishmaniasis control
Category
Poster and Podium (Block Symposium)