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Infection history imprints prolonged changes to the Kupffer cell epigenome, transcriptome and function of Kupffer cells

ABSTRACT: Background and aims: Macrophages are highly versatile innate phagocytes present in most organs of the body and perform various homeostatic and immunological functions. Macrophages are classically known for their important roles in compacting pathogens. Whereas, increasing evidence supports that exposure to infections invokes prolonged changes to tissue-resident macrophages, it remains unclear whether this occurs to liver macrophages. Methods: Here, we utilized a model of parasitic infection invoked by the protozoan parasite Trypanosoma brucei brucei to investigate whether infection history can durably reshape hepatic macrophage identity and function. Employing a combination of genetic lineage-tracing, single cell transcriptomics, epigenomic analysis, and functional assays, we studied the alterations to the liver macrophage compartment during and after the resolution of infection. Results: We show that the infection alters the composition of liver-resident macrophages, leading to the infiltration of monocytes that differentiate into various infection-associated macrophage populations with divergent transcriptomic profiles. Whereas infection-associated macrophages disappear post-resolution of infection, monocyte-derived macrophages assuming the Kupffer cell (KC)-like profile engraft in the liver and co-existed with embryonic KCs in the long-term. Remarkably, the prior exposure to infection imprinted a specific transcriptional program on post-resolution KCs that was independent of cell ontogeny. This reprogramming of KCs was driven by an epigenetic remodeling of KC chromatin landscapes and associated with altered KC function and was associated with increased resiliance to subsequent bacterial infection. Conclusion: Our study demonstrates that prior exposure to a parasitic infection can reshape the identity and function of the liver macrophage pool in the long-term.

ORGANISM(S): Mus musculus

PROVIDER: GSE266225 | GEO | 2024/08/12

REPOSITORIES: GEO

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Project description:There is an evident, unmet need to develop a commercially available in vitro system that can model inflammatory states of the liver and predict immune-mediated hepatotoxicity of drugs and xenobiotics taken under inflamed conditions. Hepatocyte-Kupffer cell co-cultures can model inflammation-mediated hepatotoxicity; however, Kupffer cell (KC) source remains an important bottleneck for the development of such models. Primary human Kupffer cells (PHKCs) are costly, limited in availability and exhibit donor variability. An alternative cell source for KCs has not been reported. Important paradigm shift from the classical dogma of adult blood-circulating monocyte-derived macrophages to intrahepatic precursor/fetal monocyte-derived macrophages has shed new light into the origin of KCs in vivo. Based on these recent findings, we report here, a novel method to generate human KCs in vitro from stem cells (hPSC-KCs) via fetal monocytes. hPSC-KCs expressed macrophage markers, CD11, CD14, CD68, CD163 and CD32 at gene and protein level and exhibited functional properties such as phagocytosis and Interleukin-6 and Tumor Necrosis Factor-4alpha production upon activation. Importantly, molecular signature, liver-macrophage specific CLEC-4F expression and cytokines production levels of hPSC-KCs were similar to PHKCs but different from non-liver macrophages. We used an inflammatory liver co-culture model to demonstrate that activated hPSC-KCs, but not non-liver macrophages, were able to recapitulate effects of PHKCs when stimulated with paradigm hepatotoxicants. hPSC-KCs developed in this study offer a renewable human cell source for liver-specific macrophages which can be used to develop in vitro systems for modelling the inflammatory state of the liver. Gene expression profiles of 9 samples were determined using Human Gene 2.0 ST Array. These 9 samples included three replicates each of PHKCs (primary human Kupffer cells), human pluripotent stem cell-dervied Kupffer cells (hPSC-KCs) and non-liver macrophages (NL-Mφ).

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Infection history imprints prolonged changes to the Kupffer cell epigenome, transcriptome and function of Kupffer cells

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