Human monocyte-derived dendritic cells turn into foamy dendritic cells with IL-17A

Salvatore, Giulia; Bernoud-Hubac, Nathalie; Bissay, Nathalie; Debard, Cyrille; Daira, Patricia; Meugnier, Emmanuelle; Proamer, Fabienne; Hanau, Daniel; Vidal, Hubert; Aricò, Maurizio; Delprat, Christine; Mahtouk, Karène

doi:10.1194/jlr.m054874

Cited by 21 publications

(14 citation statements)

References 47 publications

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“…IL-17A is considered to be proatherogenic and is found to be involved in the formation of foamy macrophages 22 . Recently Salvatore et al found that IL-17A turned monocyte derived dendritic cells into foamy dendritic cells by increased cholesterol uptake 23 . Here, in-vitro studies on keratinocytes were further validated on psoriatic skin and we found elevated levels of cholesterol in psoriatic lesional skin and decreased expression of cholesterol and fatty acid related genes.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome profiling unveils the role of cholesterol in IL-17A signaling in psoriasis

Varshney

Narasimhan

Mittal

et al. 2016

Sci Rep

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Psoriasis is a chronic inflammatory skin disease characterized by altered proliferation and differentiation of keratinocytes as well as infiltration of immune cells. Increased expression of Th17 cells and cytokines secreted by them provides evidence for its central role in the pathogenesis of psoriasis. IL-17A, signature cytokine of Th17 cells was found to be highly differentially expressed in psoriatic lesional skin. However, cellular and molecular mechanism by which IL-17A exerts its function on keratinocyte is incompletely understood. To understand IL-17A mediated signal transduction pathways, gene expression profiling was done and differentially expressed genes were analysed by IPA software. Here, we demonstrate that during IL-17A signaling total cholesterol levels were elevated, which in turn resulted in the suppression of genes of cholesterol and fatty acid biosynthesis. We found that accumulation of cholesterol was essential for IL-17A signaling as reduced total cholesterol levels by methyl β cyclodextrin (MBCD), significantly decreased IL-17A induced secretion of CCL20, IL-8 and S100A7 from the keratinocytes. To our knowledge this study for the first time unveils that high level of intracellular cholesterol plays a crucial role in IL-17A signaling in keratinocytes and may explain the strong association between psoriasis and dyslipidemia.

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Section: Discussionmentioning

confidence: 99%

Transcriptome profiling unveils the role of cholesterol in IL-17A signaling in psoriasis

Varshney

Narasimhan

Mittal

et al. 2016

Sci Rep

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“…It has been demonstrated that IL‐17 stimulation increases the expression of Msr‐1 and other genes related to lipid metabolism, increasing the number of LDs. However, IL‐17 stimulation did change the expression of MHC proteins . Similarly, the accumulation of TAG in dendritic cells stimulated with tumor explant supernatants was dependent on its uptake mediated by Msr‐1, which was increased in dendritic cells from tumor‐bearing mice.…”

Section: Lds and Antigen Presentationmentioning

confidence: 91%

“…However, IL-17 stimulation did change the expression of MHC proteins. 204 Similarly, the accumulation of TAG in dendritic cells stimulated with tumor explant supernatants was dependent on its uptake mediated by Msr-1, which was increased in dendritic cells from tumor-bearing mice. In this work, the authors showed that dendritic cells generated from Msr-1 −/− mice failed to accumulate lipids after transfer to tumor-bearing recipients and were more effective in Tcell activation.…”

Section: Lds and Antigen Presentationmentioning

confidence: 93%

Fat, fight, and beyond: The multiple roles of lipid droplets in infections and inflammation

Pereira-Dutra

Teixeira

Costa

et al. 2019

Journal of Leukocyte Biology

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Increased accumulation of cytoplasmic lipid droplets (LDs) in host nonadipose cells is commonly observed in response to numerous infectious diseases, including bacterial, parasite, and fungal infections. LDs are lipid‐enriched, dynamic organelles composed of a core of neutral lipids surrounded by a monolayer of phospholipids associated with a diverse array of proteins that are cell and stimulus regulated. Far beyond being simply a deposit of neutral lipids, LDs have come to be seen as an essential platform for various cellular processes, including metabolic regulation, cell signaling, and the immune response. LD participation in the immune response occurs as sites for compartmentalization of several immunometabolic signaling pathways, production of inflammatory lipid mediators, and regulation of antigen presentation. Infection‐driven LD biogenesis is a complexly regulated process that involves innate immune receptors, transcriptional and posttranscriptional regulation, increased lipid uptake, and new lipid synthesis. Accumulating evidence demonstrates that intracellular pathogens are able to exploit LDs as an energy source, a replication site, and/or a mechanism of immune response evasion. Nevertheless, LDs can also act in favor of the host as part of the immune and inflammatory response to pathogens. Here, we review recent findings that explored the new roles of LDs in the context of host‐pathogen interactions.

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“…These studies demonstrated an increase in the expression and production of cytokines resulting from the interaction of macrophages with modified lipoproteins. Accumulating evidence suggested that it is likely that some pro-inflammatory cytokines may be involved in the formation of foam cells [44][45][46]. Moreover, here, we included further experiments testing the knockdown effect of five pro-inflammatory molecule-encoding genes identified in our previous study [19], such as IL15, EIF2AK3, F2RL1, TSPYL2, and ANXA1, on LDL accumulation, that can help to elucidate the relationship between the inflammatory immune response and the accumulation of cholesterol during the formation of foam cells (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

Role of Phagocytosis in the Pro-Inflammatory Response in LDL-Induced Foam Cell Formation; a Transcriptome Analysis

Orekhov

Nikiforov

Sukhorukov

et al. 2020

IJMS

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Excessive accumulation of lipid inclusions in the arterial wall cells (foam cell formation) caused by modified low-density lipoprotein (LDL) is the earliest and most noticeable manifestation of atherosclerosis. The mechanisms of foam cell formation are not fully understood and can involve altered lipid uptake, impaired lipid metabolism, or both. Recently, we have identified the top 10 master regulators that were involved in the accumulation of cholesterol in cultured macrophages induced by the incubation with modified LDL. It was found that most of the identified master regulators were related to the regulation of the inflammatory immune response, but not to lipid metabolism. A possible explanation for this unexpected result is a stimulation of the phagocytic activity of macrophages by modified LDL particle associates that have a relatively large size. In the current study, we investigated gene regulation in macrophages using transcriptome analysis to test the hypothesis that the primary event occurring upon the interaction of modified LDL and macrophages is the stimulation of phagocytosis, which subsequently triggers the pro-inflammatory immune response. We identified genes that were up- or downregulated following the exposure of cultured cells to modified LDL or latex beads (inert phagocytosis stimulators). Most of the identified master regulators were involved in the innate immune response, and some of them were encoding major pro-inflammatory proteins. The obtained results indicated that pro-inflammatory response to phagocytosis stimulation precedes the accumulation of intracellular lipids and possibly contributes to the formation of foam cells. In this way, the currently recognized hypothesis that the accumulation of lipids triggers the pro-inflammatory response was not confirmed. Comparative analysis of master regulators revealed similarities in the genetic regulation of the interaction of macrophages with naturally occurring LDL and desialylated LDL. Oxidized and desialylated LDL affected a different spectrum of genes than naturally occurring LDL. These observations suggest that desialylation is the most important modification of LDL occurring in vivo. Thus, modified LDL caused the gene regulation characteristic of the stimulation of phagocytosis. Additionally, the knock-down effect of five master regulators, such as IL15, EIF2AK3, F2RL1, TSPYL2, and ANXA1, on intracellular lipid accumulation was tested. We knocked down these genes in primary macrophages derived from human monocytes. The addition of atherogenic naturally occurring LDL caused a significant accumulation of cholesterol in the control cells. The knock-down of the EIF2AK3 and IL15 genes completely prevented cholesterol accumulation in cultured macrophages. The knock-down of the ANXA1 gene caused a further decrease in cholesterol content in cultured macrophages. At the same time, knock-down of F2RL1 and TSPYL2 did not cause an effect. The results obtained allowed us to explain in which way the inflammatory response and the accumulation of cholesterol are related confirming our hypothesis of atherogenesis development based on the following viewpoints: LDL particles undergo atherogenic modifications that, in turn, accompanied by the formation of self-associates; large LDL associates stimulate phagocytosis; as a result of phagocytosis stimulation, pro-inflammatory molecules are secreted; these molecules cause or at least contribute to the accumulation of intracellular cholesterol. Therefore, it became obvious that the primary event in this sequence is not the accumulation of cholesterol but an inflammatory response.

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Human monocyte-derived dendritic cells turn into foamy dendritic cells with IL-17A

Cited by 21 publications

References 47 publications

Transcriptome profiling unveils the role of cholesterol in IL-17A signaling in psoriasis

Transcriptome profiling unveils the role of cholesterol in IL-17A signaling in psoriasis

Fat, fight, and beyond: The multiple roles of lipid droplets in infections and inflammation

Role of Phagocytosis in the Pro-Inflammatory Response in LDL-Induced Foam Cell Formation; a Transcriptome Analysis

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