Cargando…

Phagocytic Uptake of Oxidized Heme Polymer Is Highly Cytotoxic to Macrophages

Apoptosis in macrophages is responsible for immune-depression and pathological effects during malaria. Phagocytosis of PRBC causes induction of apoptosis in macrophages through release of cytosolic factors from infected cells. Heme polymer or β-hematin causes dose-dependent death of macrophages with...

Descripción completa

Detalles Bibliográficos
Autores principales: Deshmukh, Rohitas, Trivedi, Vishal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117526/
https://www.ncbi.nlm.nih.gov/pubmed/25078090
http://dx.doi.org/10.1371/journal.pone.0103706
_version_ 1782328713612886016
author Deshmukh, Rohitas
Trivedi, Vishal
author_facet Deshmukh, Rohitas
Trivedi, Vishal
author_sort Deshmukh, Rohitas
collection PubMed
description Apoptosis in macrophages is responsible for immune-depression and pathological effects during malaria. Phagocytosis of PRBC causes induction of apoptosis in macrophages through release of cytosolic factors from infected cells. Heme polymer or β-hematin causes dose-dependent death of macrophages with LC(50) of 132 µg/ml and 182 µg/ml respectively. The toxicity of hemin or heme polymer was amplified several folds in the presence of non-toxic concentration of methemoglobin. β-hematin uptake in macrophage through phagocytosis is crucial for enhanced toxicological effects in the presence of methemoglobin. Higher accumulation of β-hematin is observed in macrophages treated with β-hematin along with methemoglobin. Light and scanning electron microscopic observations further confirm accumulation of β-hematin with cellular toxicity. Toxicological potentiation of pro-oxidant molecules toward macrophages depends on generation of H(2)O(2) and independent to release of free iron from pro-oxidant molecules. Methemoglobin oxidizes β-hematin to form oxidized β-hematin (βH*) through single electron transfer mechanism. Pre-treatment of reaction mixture with spin-trap Phenyl-N-t-butyl-nitrone dose-dependently reverses the β-hematin toxicity, indicates crucial role of βH* generation with the toxicological potentiation. Acridine orange/ethidium bromide staining and DNA fragmentation analysis indicate that macrophage follows an oxidative stress dependent apoptotic pathway to cause death. In summary, current work highlights mutual co-operation between methemoglobin and different pro-oxidant molecules to enhance toxicity towards macrophages. Hence, methemoglobin peroxidase activity can be probed for subduing cellular toxicity of pro-oxidant molecules and it may in-turn make up for host immune response against the malaria parasite.
format Online
Article
Text
id pubmed-4117526
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-41175262014-08-04 Phagocytic Uptake of Oxidized Heme Polymer Is Highly Cytotoxic to Macrophages Deshmukh, Rohitas Trivedi, Vishal PLoS One Research Article Apoptosis in macrophages is responsible for immune-depression and pathological effects during malaria. Phagocytosis of PRBC causes induction of apoptosis in macrophages through release of cytosolic factors from infected cells. Heme polymer or β-hematin causes dose-dependent death of macrophages with LC(50) of 132 µg/ml and 182 µg/ml respectively. The toxicity of hemin or heme polymer was amplified several folds in the presence of non-toxic concentration of methemoglobin. β-hematin uptake in macrophage through phagocytosis is crucial for enhanced toxicological effects in the presence of methemoglobin. Higher accumulation of β-hematin is observed in macrophages treated with β-hematin along with methemoglobin. Light and scanning electron microscopic observations further confirm accumulation of β-hematin with cellular toxicity. Toxicological potentiation of pro-oxidant molecules toward macrophages depends on generation of H(2)O(2) and independent to release of free iron from pro-oxidant molecules. Methemoglobin oxidizes β-hematin to form oxidized β-hematin (βH*) through single electron transfer mechanism. Pre-treatment of reaction mixture with spin-trap Phenyl-N-t-butyl-nitrone dose-dependently reverses the β-hematin toxicity, indicates crucial role of βH* generation with the toxicological potentiation. Acridine orange/ethidium bromide staining and DNA fragmentation analysis indicate that macrophage follows an oxidative stress dependent apoptotic pathway to cause death. In summary, current work highlights mutual co-operation between methemoglobin and different pro-oxidant molecules to enhance toxicity towards macrophages. Hence, methemoglobin peroxidase activity can be probed for subduing cellular toxicity of pro-oxidant molecules and it may in-turn make up for host immune response against the malaria parasite. Public Library of Science 2014-07-31 /pmc/articles/PMC4117526/ /pubmed/25078090 http://dx.doi.org/10.1371/journal.pone.0103706 Text en © 2014 Deshmukh, Trivedi http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Deshmukh, Rohitas
Trivedi, Vishal
Phagocytic Uptake of Oxidized Heme Polymer Is Highly Cytotoxic to Macrophages
title Phagocytic Uptake of Oxidized Heme Polymer Is Highly Cytotoxic to Macrophages
title_full Phagocytic Uptake of Oxidized Heme Polymer Is Highly Cytotoxic to Macrophages
title_fullStr Phagocytic Uptake of Oxidized Heme Polymer Is Highly Cytotoxic to Macrophages
title_full_unstemmed Phagocytic Uptake of Oxidized Heme Polymer Is Highly Cytotoxic to Macrophages
title_short Phagocytic Uptake of Oxidized Heme Polymer Is Highly Cytotoxic to Macrophages
title_sort phagocytic uptake of oxidized heme polymer is highly cytotoxic to macrophages
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117526/
https://www.ncbi.nlm.nih.gov/pubmed/25078090
http://dx.doi.org/10.1371/journal.pone.0103706
work_keys_str_mv AT deshmukhrohitas phagocyticuptakeofoxidizedhemepolymerishighlycytotoxictomacrophages
AT trivedivishal phagocyticuptakeofoxidizedhemepolymerishighlycytotoxictomacrophages