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Using Mass Cytometry and In vivo Imaging to Study Emergency Repopulation of Immune Cells in Murine Liver

ABSTRACT: Macrophages and dendritic cells are phagocytes present in almost all tissues in mammals and play a pivotal role for tissue homeostasis and during immune responses. Liver phagocytes play a pivotal role in host immune responses and exquisite mechanisms are necessary to govern the density and the location of the different hepatic leukocytes. However in catastrophic events including trauma, infections or toxin ingestion, many of the liver phagocytes can be wiped out leaving large areas devoid of these cells. Here we used a unique combination of mass cytometry (CyTOF), gene expression and liver intravital approaches to precisely determine phagocytic populations within the liver and the functional consequences of their replenishment by myeloid precursors. While Kupffer cells were exclusively located in the sinusoidal lumen, we identified a population of dendritic cells that was mainly located under the liver capsule. After full depletion of dendritic and Kupffer cells, intravascular myeloid precursors replenished location, density and function of both populations. However, these emergency repopulated livers were dysfunctional in their ability to respond to injury and to clear bacteria for at least 30 days. After this “educational period”, new phagocytes returned to normal response to injury and bacterial trapping. Conclusions: Our data shed light on the liver’s ability to locally shape phagocyte precursors into two vastly different immune cells localized to two fundamentally different tissue compartments.

ORGANISM(S): Mus musculus

PROVIDER: GSE81645 | GEO | 2016/06/12

SECONDARY ACCESSION(S): PRJNA322189

REPOSITORIES: GEO

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Project description:Kupffer cells have been implicated in the pathogenesis of various liver diseases. However, their involvement in metabolic disorders of the liver, including fatty liver disease, remains unclear. The present study sought to determine the impact of Kupffer cells on hepatic triglyceride storage and to explore the possible mechanisms involved. To that end, C57Bl/6 mice rendered obese and steatotic by chronic high-fat feeding were treated for 1 week with clodronate liposomes, which cause depletion of Kupffer cells. Loss of expression of marker genes Cd68, F4/80, and Clec4f, and loss of Cd68 immunostaining verified almost complete removal of Kupffer cells from the liver. Also, expression of complement components C1, the chemokine (C-C motif) ligand 6 (Ccl6), and cytokines interleukin-15 (IL-15) and IL-1beta were markedly reduced. Importantly, Kupffer cell depletion significantly decreased liver triglyceride and glucosylceramide levels concurrent with increased expression of genes involved in fatty acid oxidation including peroxisome proliferator-activated receptor alpha (PPARalpha), carnitine palmitoyltransferase 1A (Cpt1alpha), and fatty acid transport protein 2 (Fatp2). Treatment of mice with IL-1beta decreased expression of PPARalpha and its target genes, which was confirmed in primary hepatocytes. Consistent with these data, IL-1beta suppressed human and mouse PPARalpha promoter activity. Suppression of PPARalpha promoter activity was recapitulated by overexpression of nuclear factor kappaB (NF-kappaB) subunit p50 and p65, and was abolished upon deletion of putative NF-kappaB binding sites. Finally, IL-1beta and NF-kappaB interfered with the ability of PPARalpha to activate gene transcription. CONCLUSION: Our data point toward important cross-talk between Kupffer cells and hepatocytes in the regulation of hepatic triglyceride storage. The effect of Kupffer cells on liver triglycerides are at least partially mediated by IL-1beta, which suppresses PPARalpha expression and activity. Expression profiling of livers from mice fed control, low-fat diet diet or high-fat diet for 20weeks with or without knockdown of Kupffer cells.

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Using Mass Cytometry and In vivo Imaging to Study Emergency Repopulation of Immune Cells in Murine Liver

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