Dendritic Cell Populations With Different Concentrations of Lipid Regulate Tolerance and Immunity in Mouse and Human Liver

Abstract

Background & Aims Immune cells of the liver must be able to recognize and react to pathogens yet remain tolerant to food molecules and other non-pathogens. Dendritic cells (DC) are thought to contribute to hepatic tolerance. Lipids have been implicated in dysfunction of DC in cancer. Therefore, we investigated whether high lipid content in liver DC affects induction of tolerance. Methods Mouse and human hepatic non-parenchymal cells were isolated by mechanical and enzymatic digestion. DC were purified by fluorescence-activated cell sorting or with immunomagnetic beads. DC lipid content was assessed by flow cytometry, immune fluorescence, and electron microscopy and by measuring intracellular component lipids. DC activation was determined from surface phenotype and cytokine profile. DC function was assessed in T-cell, natural killer (NK)-cell, and NKT-cell co-culture assays, as well as in vivo. Results We observed 2 distinct populations of hepatic DC in mice and humans based on their lipid content and expression of markers associated with adipogensis and lipid metabolism. This lipid-based dichotomy in DC was unique to the liver and specific to DC, compared with other hepatic immune cells. However, rather than mediate tolerance, the liver DC population with high concentrations of lipid was immunogenic in multiple models—they activated T cells, NK cells, and NKT cells. Conversely, liver DC with low levels of lipid induced T-regulatory cells, anergy to cancer, and oral tolerance. The immunogenicity of lipid-rich liver DC required their secretion of tumor necrosis factor-α and was directly related to their high lipid content; blocking DC synthesis of fatty acids or inhibiting adipogenesis (by reducing endoplasmic reticular stress) reduced DC immunogenicity. Conclusions Human and mouse hepatic DC are comprised of distinct populations that contain different concentrations of lipid, which regulates immunogenic versus tolerogenic responses in the liver.

The immunophenotype of antigen presenting cells of the mononuclear phagocyte system in normal human liver – A systematic review

“…• "Thin"-extended cytoplasm [32] • "Round"-larger cells with round cytoplasm [32] • 5 subsets defined by varying endogenous peroxidase activity and levels of endoplasmic reticulum [86] • Minimal functional experimental evidence on liver macrophages • Liver Macrophages appear to be predominantly tolerogenic in nature, with a regulatory and scavenging role [41,57,69,89] • Function inferred through observations of variable expression of antigen presenting molecules [72], lectins [33,49,55,69,92], Fc Receptors, complement receptors [70], low co-stimulatory marker expression [77] and inhibitory markers such as Z39Ig [89] Perisinusoidal [78] • [101] Tolerogenic in nature • Lower expression of costimulation markers compared to spleen [98] • Produce IL-10 on LPS stimulation [98] • Stimulate T-cells that are IL-10 producing and hypo-responsive on re-stimulation [98] • Produce higher numbers of FoxP3 + Treg cells on naïve T cell stimulation [98] • Weak MLR response compared to blood [98] Portal tract [103] • divided into subsets with different potential for antigen presentation, motility, and cytokine production, all of which can help determine the nature of the immune system's response [17]. A particular complicating factor in the case of the liver is that circulating monocytes also traffic through the sinusoids, and distinguishing between in transit monocyte subsets and other MPS subsets is an evolving science [17].…”

“…Liver dendritic cells Ten papers describe the immunophenotype of liver dendritic cells (DC) in human liver [20,51,95,[97][98][99][100][101][102][103].…”

Immunomodulatory liposomes targeting liver macrophages arrest progression of nonalcoholic steatohepatitis

“…Hepatic DCs can be similarly categorized, where DCs containing high levels of lipid are immunogenic while low-lipid DCs are tolerogenic [11].…”

Lipid-laden partially-activated plasmacytoid and CD4−CD8α+ dendritic cells accumulate in tissues in elderly mice

“…Ibrahim et al demonstrated that the lipid content of hepatic DCs was a determinant of their immunogenicity, and that lipid-laden DCs produced higher levels of TNF-α [36]. TNF-α is a powerful pro-inflammatory cytokine which is associated with numerous pathologies [37,38].…”