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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
SAGE Publications
2018
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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. |
format | Online Article Text |
id | pubmed-5777552 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | SAGE Publications |
record_format | MEDLINE/PubMed |
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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