Macrophage autophagy protects against hepatocellular carcinogenesis in mice

Abstract Autophagy is a lysosomal degradation pathway of cellular components that regulates macrophage properties. Macrophages are critically involved in tumor growth, metastasis, angiogenesis and immune suppression. Here, we investigated whether macrophage autophagy may protect against hepatocellul...

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Autores principales:	Anthony Deust, Marie-Noële Chobert, Vanessa Demontant, Guillaume Gricourt, Timothé Denaës, Allan Thiolat, Isaac Ruiz, Christophe Rodriguez, Jean-Michel Pawlotsky, Fatima Teixeira-Clerc
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8cd7e9131b554122951c0e8731db375d
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spelling	oai:doaj.org-article:8cd7e9131b554122951c0e8731db375d2021-12-02T15:14:55ZMacrophage autophagy protects against hepatocellular carcinogenesis in mice10.1038/s41598-021-98203-52045-2322https://doaj.org/article/8cd7e9131b554122951c0e8731db375d2021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-98203-5https://doaj.org/toc/2045-2322Abstract Autophagy is a lysosomal degradation pathway of cellular components that regulates macrophage properties. Macrophages are critically involved in tumor growth, metastasis, angiogenesis and immune suppression. Here, we investigated whether macrophage autophagy may protect against hepatocellular carcinoma (HCC). Experiments were performed in mice with deletion of the autophagy gene Atg5 in the myeloid lineage (ATG5Mye−/− mice) and their wild-type (WT) littermates. As compared to WT, ATG5Mye−/− mice were more susceptible to diethylnitrosamine (DEN)-induced hepatocarcinogenesis, as shown by enhanced tumor number and volume. Moreover, DEN-treated ATG5Mye−/− mice exhibited compromised immune cell recruitment and activation in the liver, suggesting that macrophage autophagy invalidation altered the antitumoral immune response. RNA sequencing showed that autophagy-deficient macrophages sorted from DEN mice are characterized by an enhanced expression of immunosuppressive markers. In vitro studies demonstrated that hepatoma cells impair the autophagy flux of macrophages and stimulate their expression of programmed cell death-ligand 1 (PD-L1), a major regulator of the immune checkpoint. Moreover, pharmacological activation of autophagy reduces hepatoma cell-induced PD-L1 expression in cultured macrophages while inhibition of autophagy further increases PD-L1 expression suggesting that autophagy invalidation in macrophages induces an immunosuppressive phenotype. These results uncover macrophage autophagy as a novel protective pathway regulating liver carcinogenesis.Anthony DeustMarie-Noële ChobertVanessa DemontantGuillaume GricourtTimothé DenaësAllan ThiolatIsaac RuizChristophe RodriguezJean-Michel PawlotskyFatima Teixeira-ClercNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Anthony Deust Marie-Noële Chobert Vanessa Demontant Guillaume Gricourt Timothé Denaës Allan Thiolat Isaac Ruiz Christophe Rodriguez Jean-Michel Pawlotsky Fatima Teixeira-Clerc Macrophage autophagy protects against hepatocellular carcinogenesis in mice
description	Abstract Autophagy is a lysosomal degradation pathway of cellular components that regulates macrophage properties. Macrophages are critically involved in tumor growth, metastasis, angiogenesis and immune suppression. Here, we investigated whether macrophage autophagy may protect against hepatocellular carcinoma (HCC). Experiments were performed in mice with deletion of the autophagy gene Atg5 in the myeloid lineage (ATG5Mye−/− mice) and their wild-type (WT) littermates. As compared to WT, ATG5Mye−/− mice were more susceptible to diethylnitrosamine (DEN)-induced hepatocarcinogenesis, as shown by enhanced tumor number and volume. Moreover, DEN-treated ATG5Mye−/− mice exhibited compromised immune cell recruitment and activation in the liver, suggesting that macrophage autophagy invalidation altered the antitumoral immune response. RNA sequencing showed that autophagy-deficient macrophages sorted from DEN mice are characterized by an enhanced expression of immunosuppressive markers. In vitro studies demonstrated that hepatoma cells impair the autophagy flux of macrophages and stimulate their expression of programmed cell death-ligand 1 (PD-L1), a major regulator of the immune checkpoint. Moreover, pharmacological activation of autophagy reduces hepatoma cell-induced PD-L1 expression in cultured macrophages while inhibition of autophagy further increases PD-L1 expression suggesting that autophagy invalidation in macrophages induces an immunosuppressive phenotype. These results uncover macrophage autophagy as a novel protective pathway regulating liver carcinogenesis.
format	article
author	Anthony Deust Marie-Noële Chobert Vanessa Demontant Guillaume Gricourt Timothé Denaës Allan Thiolat Isaac Ruiz Christophe Rodriguez Jean-Michel Pawlotsky Fatima Teixeira-Clerc
author_facet	Anthony Deust Marie-Noële Chobert Vanessa Demontant Guillaume Gricourt Timothé Denaës Allan Thiolat Isaac Ruiz Christophe Rodriguez Jean-Michel Pawlotsky Fatima Teixeira-Clerc
author_sort	Anthony Deust
title	Macrophage autophagy protects against hepatocellular carcinogenesis in mice
title_short	Macrophage autophagy protects against hepatocellular carcinogenesis in mice
title_full	Macrophage autophagy protects against hepatocellular carcinogenesis in mice
title_fullStr	Macrophage autophagy protects against hepatocellular carcinogenesis in mice
title_full_unstemmed	Macrophage autophagy protects against hepatocellular carcinogenesis in mice
title_sort	macrophage autophagy protects against hepatocellular carcinogenesis in mice
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/8cd7e9131b554122951c0e8731db375d
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Macrophage autophagy protects against hepatocellular carcinogenesis in mice

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