Intestinal Intervention Strategy Targeting Myeloid Cells to Improve Hepatic Immunity during Hepatocarcinoma Development

Innate immunity in the tumor microenvironment plays a pivotal role in hepatocarcinoma (HCC) progression. Plant seeds provide serine-type protease inhibitors (SETIs), which can have a significant influence on liver inflammation and macrophage function. To elucidate the influence of SETIs to counter p...

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Autores principales:	Adrián Bouzas Muñoz, Juan Antonio Giménez-Bastida, Aurora García Tejedor, Claudia Monika Haros, Marta Gómez de Cedrón, Ana Ramírez de Molina, José Moisés Laparra Llopis
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	macrophages lipid homeostasis immunonutrition hepatocarcinoma Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/bbe26387b2f44aa19a21d7e1759feafe
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spelling	oai:doaj.org-article:bbe26387b2f44aa19a21d7e1759feafe2021-11-25T16:49:51ZIntestinal Intervention Strategy Targeting Myeloid Cells to Improve Hepatic Immunity during Hepatocarcinoma Development10.3390/biomedicines91116332227-9059https://doaj.org/article/bbe26387b2f44aa19a21d7e1759feafe2021-11-01T00:00:00Zhttps://www.mdpi.com/2227-9059/9/11/1633https://doaj.org/toc/2227-9059Innate immunity in the tumor microenvironment plays a pivotal role in hepatocarcinoma (HCC) progression. Plant seeds provide serine-type protease inhibitors (SETIs), which can have a significant influence on liver inflammation and macrophage function. To elucidate the influence of SETIs to counter pro-tumorigenic conditions, at the early stages of HCC development, it was used as an established model of diethylnitrosamine/thioacetamide-injured liver fed with a standard diet (STD) or high-fat diet (42%) (HFD). The administration of SETIs improved survival and ameliorated tumor burden via modulation of monocyte-derived macrophages as key effectors involved in diet-induced HCC development. RT-qPCR analyses of hepatic tissue evidenced a diet-independent downregulatory effect of SETIs on the transcripts of CD36, FASN, ALOX15, and SREBP1c; however, animals fed with an STD showed opposing effects for PPAR and NRLP3 levels. These effects were accompanied by a decreased production of IL-6 and IL-17 but increased that of TNF in animals receiving SETIs. Moreover, only animals fed an HFD displayed increased concentrations of the stem cell factor. Overall, SETIs administration decreased the hepatic contents of lysophosphatydilcholine, phosphatidylinositol, phosphatidylcholine, and phosphatidyl ethanolamine. Notably, animals that received SETIs exhibited increased hepatic proportions of CD68<sup>+</sup>CX3CR1<sup>+</sup>CD74<sup>+</sup> cells and at a higher rate in those animals fed an HFD. Altogether, the data evidence that oral administration of SETIs modulates the tumor microenvironment, improving hepatic innate immune response(s) and favoring a better antitumoral environment. It represents a path forward in developing coadjutant strategies to pharmacological therapies, with either a preventive or therapeutic character, to counter physiopathological conditions at early stages of HCC development.Adrián Bouzas MuñozJuan Antonio Giménez-BastidaAurora García TejedorClaudia Monika HarosMarta Gómez de CedrónAna Ramírez de MolinaJosé Moisés Laparra LlopisMDPI AGarticlemacrophageslipid homeostasisimmunonutritionhepatocarcinomaBiology (General)QH301-705.5ENBiomedicines, Vol 9, Iss 1633, p 1633 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	macrophages lipid homeostasis immunonutrition hepatocarcinoma Biology (General) QH301-705.5
spellingShingle	macrophages lipid homeostasis immunonutrition hepatocarcinoma Biology (General) QH301-705.5 Adrián Bouzas Muñoz Juan Antonio Giménez-Bastida Aurora García Tejedor Claudia Monika Haros Marta Gómez de Cedrón Ana Ramírez de Molina José Moisés Laparra Llopis Intestinal Intervention Strategy Targeting Myeloid Cells to Improve Hepatic Immunity during Hepatocarcinoma Development
description	Innate immunity in the tumor microenvironment plays a pivotal role in hepatocarcinoma (HCC) progression. Plant seeds provide serine-type protease inhibitors (SETIs), which can have a significant influence on liver inflammation and macrophage function. To elucidate the influence of SETIs to counter pro-tumorigenic conditions, at the early stages of HCC development, it was used as an established model of diethylnitrosamine/thioacetamide-injured liver fed with a standard diet (STD) or high-fat diet (42%) (HFD). The administration of SETIs improved survival and ameliorated tumor burden via modulation of monocyte-derived macrophages as key effectors involved in diet-induced HCC development. RT-qPCR analyses of hepatic tissue evidenced a diet-independent downregulatory effect of SETIs on the transcripts of CD36, FASN, ALOX15, and SREBP1c; however, animals fed with an STD showed opposing effects for PPAR and NRLP3 levels. These effects were accompanied by a decreased production of IL-6 and IL-17 but increased that of TNF in animals receiving SETIs. Moreover, only animals fed an HFD displayed increased concentrations of the stem cell factor. Overall, SETIs administration decreased the hepatic contents of lysophosphatydilcholine, phosphatidylinositol, phosphatidylcholine, and phosphatidyl ethanolamine. Notably, animals that received SETIs exhibited increased hepatic proportions of CD68<sup>+</sup>CX3CR1<sup>+</sup>CD74<sup>+</sup> cells and at a higher rate in those animals fed an HFD. Altogether, the data evidence that oral administration of SETIs modulates the tumor microenvironment, improving hepatic innate immune response(s) and favoring a better antitumoral environment. It represents a path forward in developing coadjutant strategies to pharmacological therapies, with either a preventive or therapeutic character, to counter physiopathological conditions at early stages of HCC development.
format	article
author	Adrián Bouzas Muñoz Juan Antonio Giménez-Bastida Aurora García Tejedor Claudia Monika Haros Marta Gómez de Cedrón Ana Ramírez de Molina José Moisés Laparra Llopis
author_facet	Adrián Bouzas Muñoz Juan Antonio Giménez-Bastida Aurora García Tejedor Claudia Monika Haros Marta Gómez de Cedrón Ana Ramírez de Molina José Moisés Laparra Llopis
author_sort	Adrián Bouzas Muñoz
title	Intestinal Intervention Strategy Targeting Myeloid Cells to Improve Hepatic Immunity during Hepatocarcinoma Development
title_short	Intestinal Intervention Strategy Targeting Myeloid Cells to Improve Hepatic Immunity during Hepatocarcinoma Development
title_full	Intestinal Intervention Strategy Targeting Myeloid Cells to Improve Hepatic Immunity during Hepatocarcinoma Development
title_fullStr	Intestinal Intervention Strategy Targeting Myeloid Cells to Improve Hepatic Immunity during Hepatocarcinoma Development
title_full_unstemmed	Intestinal Intervention Strategy Targeting Myeloid Cells to Improve Hepatic Immunity during Hepatocarcinoma Development
title_sort	intestinal intervention strategy targeting myeloid cells to improve hepatic immunity during hepatocarcinoma development
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/bbe26387b2f44aa19a21d7e1759feafe
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Intestinal Intervention Strategy Targeting Myeloid Cells to Improve Hepatic Immunity during Hepatocarcinoma Development

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