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...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4117526?pdf=render |
| _version_ | 1818360199866482688 |
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| author | Rohitas Deshmukh Vishal Trivedi |
| author_facet | Rohitas Deshmukh Vishal Trivedi |
| author_sort | Rohitas Deshmukh |
| collection | DOAJ |
| 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 LC50 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 H2O2 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. |
| first_indexed | 2024-12-13T20:57:00Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-13T20:57:00Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-454f3355636940b1a60352782e0b70162022-12-21T23:31:43ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0197e10370610.1371/journal.pone.0103706Phagocytic uptake of oxidized heme polymer is highly cytotoxic to macrophages.Rohitas DeshmukhVishal TrivediApoptosis 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 LC50 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 H2O2 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.http://europepmc.org/articles/PMC4117526?pdf=render |
| spellingShingle | Rohitas Deshmukh Vishal Trivedi Phagocytic uptake of oxidized heme polymer is highly cytotoxic to macrophages. PLoS ONE |
| 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 |
| url | http://europepmc.org/articles/PMC4117526?pdf=render |
| work_keys_str_mv | AT rohitasdeshmukh phagocyticuptakeofoxidizedhemepolymerishighlycytotoxictomacrophages AT vishaltrivedi phagocyticuptakeofoxidizedhemepolymerishighlycytotoxictomacrophages |