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Polarized macrophage subsets differentially express the drug efflux transporters MRP1 and BCRP, resulting in altered HIV production

INTRODUCTION: Macrophages play an important role in HIV, where they are a cellular reservoir. Macrophages are polarized into two phenotypes: pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages, which may have altered expression of drug efflux transporters, including BCRP and MRP1. T...

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Autores principales: He, Hui, Buckley, Merrion, Britton, Bernard, Mu, Ying, Warner, Kristin, Kumar, Santosh, Cory, Theodore J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777552/
https://www.ncbi.nlm.nih.gov/pubmed/29343083
http://dx.doi.org/10.1177/2040206617745168
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author He, Hui
Buckley, Merrion
Britton, Bernard
Mu, Ying
Warner, Kristin
Kumar, Santosh
Cory, Theodore J
author_facet He, Hui
Buckley, Merrion
Britton, Bernard
Mu, Ying
Warner, Kristin
Kumar, Santosh
Cory, Theodore J
author_sort He, Hui
collection PubMed
description INTRODUCTION: Macrophages play an important role in HIV, where they are a cellular reservoir. Macrophages are polarized into two phenotypes: pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages, which may have altered expression of drug efflux transporters, including BCRP and MRP1. These differences may result in subtherapeutic concentrations of antiretrovirals inside of macrophages and viral replication. METHODS: U937 and U1 cells were polarized to the M1 or M2 phenotype via IFN-γ and LPS, or IL-4, IL-13, and LPS. Transporter expression was assessed via PCR and Western blotting, and transporter function was assessed via fluorescent dye assays. Transporter function was blocked with the inhibitors MK571 or KO143. Protein expression was confirmed in monocyte-derived macrophages. p24 production was assessed in U1 cells via enzyme-linked immunosorbent assay. RESULTS: mRNA and protein analysis demonstrated higher expression of MRP1 in M1 macrophages, while BCRP expression was downregulated in M1 macrophages. Treatment with inhibitors of transporter function decreased the difference in intracellular fluorescence between polarized macrophages. Differences in protein expression, which were observed with U937 cells, were confirmed in monocyte-derived macrophages. M1, but not M2 cells treated with MK571, showed decreased p24 production, consistent with reported MRP1 transporter expression. CONCLUSIONS: These results support our hypothesis that there is differential expression of MRP1 and BCRP on M1 and M2 polarized macrophages and suggests that these differences may result in altered intracellular concentrations of antiretrovirals in macrophages and alter viral production in these cells. Targeting these differences may be a strategy to decrease viral replication in HIV-infected individuals.
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spelling pubmed-57775522018-02-05 Polarized macrophage subsets differentially express the drug efflux transporters MRP1 and BCRP, resulting in altered HIV production He, Hui Buckley, Merrion Britton, Bernard Mu, Ying Warner, Kristin Kumar, Santosh Cory, Theodore J Antivir Chem Chemother Original Article INTRODUCTION: Macrophages play an important role in HIV, where they are a cellular reservoir. Macrophages are polarized into two phenotypes: pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages, which may have altered expression of drug efflux transporters, including BCRP and MRP1. These differences may result in subtherapeutic concentrations of antiretrovirals inside of macrophages and viral replication. METHODS: U937 and U1 cells were polarized to the M1 or M2 phenotype via IFN-γ and LPS, or IL-4, IL-13, and LPS. Transporter expression was assessed via PCR and Western blotting, and transporter function was assessed via fluorescent dye assays. Transporter function was blocked with the inhibitors MK571 or KO143. Protein expression was confirmed in monocyte-derived macrophages. p24 production was assessed in U1 cells via enzyme-linked immunosorbent assay. RESULTS: mRNA and protein analysis demonstrated higher expression of MRP1 in M1 macrophages, while BCRP expression was downregulated in M1 macrophages. Treatment with inhibitors of transporter function decreased the difference in intracellular fluorescence between polarized macrophages. Differences in protein expression, which were observed with U937 cells, were confirmed in monocyte-derived macrophages. M1, but not M2 cells treated with MK571, showed decreased p24 production, consistent with reported MRP1 transporter expression. CONCLUSIONS: These results support our hypothesis that there is differential expression of MRP1 and BCRP on M1 and M2 polarized macrophages and suggests that these differences may result in altered intracellular concentrations of antiretrovirals in macrophages and alter viral production in these cells. Targeting these differences may be a strategy to decrease viral replication in HIV-infected individuals. SAGE Publications 2018-01-17 /pmc/articles/PMC5777552/ /pubmed/29343083 http://dx.doi.org/10.1177/2040206617745168 Text en © The Author(s) 2018 http://creativecommons.org/licenses/by-nc/4.0/ Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Original Article
He, Hui
Buckley, Merrion
Britton, Bernard
Mu, Ying
Warner, Kristin
Kumar, Santosh
Cory, Theodore J
Polarized macrophage subsets differentially express the drug efflux transporters MRP1 and BCRP, resulting in altered HIV production
title Polarized macrophage subsets differentially express the drug efflux transporters MRP1 and BCRP, resulting in altered HIV production
title_full Polarized macrophage subsets differentially express the drug efflux transporters MRP1 and BCRP, resulting in altered HIV production
title_fullStr Polarized macrophage subsets differentially express the drug efflux transporters MRP1 and BCRP, resulting in altered HIV production
title_full_unstemmed Polarized macrophage subsets differentially express the drug efflux transporters MRP1 and BCRP, resulting in altered HIV production
title_short Polarized macrophage subsets differentially express the drug efflux transporters MRP1 and BCRP, resulting in altered HIV production
title_sort polarized macrophage subsets differentially express the drug efflux transporters mrp1 and bcrp, resulting in altered hiv production
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777552/
https://www.ncbi.nlm.nih.gov/pubmed/29343083
http://dx.doi.org/10.1177/2040206617745168
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