Lipid bodies containing oxidatively truncated lipids block antigen cross-presentation by dendritic cells in cancer

Veglia, Filippo; Tyurin, Vladimir A.; Mohammadyani, Dariush; Blasi, Maria Di; Duperret, Elizabeth K.; Donthireddy, Laxminarasimha; Hashimoto, Ayumi; Kapralov, Alexandr A.; Amoscato, Andrew A.; Angelini, Roberto; Patel, S.; Alicea-Torres, Kevin; Weiner, David B.; Murphy, Maureen E.; Klein‐Seetharaman, Judith; Celis, Esteban; Kagan, Valerian E.; Gabrilovich, Dmitry I.

doi:10.1038/s41467-017-02186-9

Cited by 201 publications

(163 citation statements)

References 63 publications

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“…201 This work suggests that not only the presence of LDs in dendritic cells but also their composition may be involved in LD function in the modulation of immune responses. In support of this finding, Veglia et al 202 reported that oxidized lipids stored in LDs can inhibit cross-presentation in dendritic cells in cancer, indicating that not only the type of lipids but also the oxidative state of these in LDs has implications in antigenic presentation.…”

Section: Lds and Antigen Presentationmentioning

confidence: 78%

“…Other studies have correlated lipid content with Ag presentation by dendritic cells. Ibrahim et al . demonstrated that two different dendritic cell populations can be distinguished by lipid content in mouse and human livers, one with high and another with low lipid content.…”

Section: Lds and Antigen Presentationmentioning

confidence: 99%

“…199 Other studies have correlated lipid content with Ag presentation by dendritic cells. Ibrahim et al 202 demonstrated that two different dendritic cell populations can be distinguished by lipid content in mouse and human livers, one with high and another with low lipid content. Moreover, the proportion of these 2 populations of dendritic cells in the liver was dependent on states associated with the lipid content of hepatic microenvironment.…”

Section: Lds and Antigen Presentationmentioning

confidence: 99%

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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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Section: Lds and Antigen Presentationmentioning

confidence: 78%

Section: Lds and Antigen Presentationmentioning

confidence: 99%

Section: Lds and Antigen Presentationmentioning

confidence: 99%

See 1 more Smart Citation

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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“…This phenomenon can be explained through the presence of oxidatively truncated lipids (ox‐tr‐LB) in LDs. The covalent binding of ox‐tr‐LB and chaperone heat‐shock protein 70 blocks the translocation of pMHC to the cell surface, thus preventing DCs from presenting antigen to CD8 T cells (Veglia et al , ). In the present study, we found that both, the blockage of LDs formation via iDGAT and the degradation of LDs via ATGL and MAGL inhibitors, sufficiently inhibited the maturation, mitochondrial respiration, as well as suppressive function of myeloid cells.…”

Section: Discussionmentioning

confidence: 99%

Lipid droplet‐dependent fatty acid metabolism controls the immune suppressive phenotype of tumor‐associated macrophages

et al. 2019

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Tumor‐associated macrophages (TAMs) promote tumor growth and metastasis by suppressing tumor immune surveillance. Herein, we provide evidence that the immunosuppressive phenotype of TAMs is controlled by long‐chain fatty acid metabolism, specifically unsaturated fatty acids, here exemplified by oleate. Consequently, en‐route enriched lipid droplets were identified as essential organelles, which represent effective targets for chemical inhibitors to block in vitro polarization of TAMs and tumor growth in vivo. In line, analysis of human tumors revealed that myeloid cells infiltrating colon cancer but not gastric cancer tissue indeed accumulate lipid droplets. Mechanistically, our data indicate that oleate‐induced polarization of myeloid cells depends on the mammalian target of the rapamycin pathway. Thus, our findings reveal an alternative therapeutic strategy by targeting the pro‐tumoral myeloid cells on a metabolic level.

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“…35,36 To this end, Veglia and colleagues have recently shown that lipid bodies accumulation within cancer-associated dendritic cells hinders MHC trafficking from the phagosome/lysosome to the cell surface, thereby jeopardizing dendritic cells capacity at stimulating antigen-specific T-cell expansion. 37 Finally, the use of a diet-induced model of NASH could be criticized as it may not fully recapitulate the precise pathophysiology of human NASH.…”

Section: Discussionmentioning

confidence: 99%

Tolerogenic properties of liver macrophages in non‐alcoholic steatohepatitis

Orci

Kreutzfeldt

Goossens

et al. 2020

Liver International

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Background & Aims Our understanding of non‐alcoholic fatty liver disease (NAFLD) pathogenesis is improving, but there is still limited data on the function of resident liver macrophages in this context, especially when considering their contribution in dampening liver inflammation. Methods Liver macrophages were studied in mouse models of prolonged diet‐induced liver steatohepatitis and carbon tetrachloride‐induced liver injury. We assessed liver macrophages phenotype and costimulatory/inhibitory properties upon exposure to lipopolysaccharide or interleukin 4. We did phagocytosis and antigen presentation assays to investigate liver macrophages function as scavengers and immune response initiators. Using immunofluorescence staining, we further determined, in human liver tissue of patients with simple steatosis, non‐alcoholic steatohepatitis and chronic hepatitis B infection, the expression of the co‐inhibitory protein CD274 (Programmed‐death ligand 1) and major histocompatibility complex (MHC) class II. Results Both in humans and mice, within chronically inflamed fatty livers, liver macrophages acquired immunomodulatory properties by reducing the expression of MHC class II, and by enhancing co‐inhibitory signalling. Liver macrophages circumscribed endotoxin‐mediated inflammatory response by upregulating anti‐inflammatory genes arginase 1 and interleukin‐10. While hepatic macrophages isolated from mice with normal livers were capable of achieving endotoxin tolerance, our results indicated an impairment of this protective mechanism in the presence NASH‐like parenchymal abnormalities. Conclusions Liver macrophages can achieve endotoxin tolerance, but in the chronically inflamed fatty liver, while they acquire an immunomodulatory phenotype, liver macrophages fail to dampen immune‐mediated damage. Therefore, loss of tolerogenicity induced by ongoing liver insult may be a mechanism contributing to the worsening of NAFLD.

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Lipid bodies containing oxidatively truncated lipids block antigen cross-presentation by dendritic cells in cancer

Cited by 201 publications

References 63 publications

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

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

Lipid droplet‐dependent fatty acid metabolism controls the immune suppressive phenotype of tumor‐associated macrophages

Tolerogenic properties of liver macrophages in non‐alcoholic steatohepatitis

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