| Heme induces programmed necrosis on macrophages through autocrine TNF and ROS production. | |
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MedLine Citation:
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PMID: 22262768 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Diseases that cause hemolysis or myonecrosis lead to the leakage of large amounts of heme proteins. Free heme has proinflammatory and cytotoxic effects. Heme induces TLR4-dependent production of TNF, whereas heme cytotoxicity has been attributed to its ability to intercalate into cell membranes and cause oxidative stress. Here we showed that heme caused early macrophage death characterized by the loss of plasma membrane integrity and morphological features resembling necrosis. Heme-induced cell death required TNFR1 and TLR4/MyD88-dependent TNF production. Addition of TNF to Tlr4-/- or to Myd88-/- macrophages restored heme-induced cell death. The use of necrostatin-1, a selective inhibitor of receptor-interacting protein 1 (RIP1, also know as RIPK1), or cells deficient in Rip1 or Rip3 revealed a critical role for RIP proteins in heme-induced cell death. Serum, antioxidants, iron chelation or inhibition of JNK ameliorated heme-induced oxidative burst and blocked macrophage cell death. Macrophages from heme oxygenase-1 deficient mice (Hmox1-/-) had increased oxidative stress and were more sensitive to heme. Taken together, these results revealed that heme induces macrophage necrosis through two synergistic mechanisms: TLR4/Myd88-dependent expression of TNF and TLR4-independent generation of ROS. |
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Authors:
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Guilherme B Fortes; Leticia S Alves; Rosane de Oliveira; Fabianno F Dutra; Danielle Rodrigues; Patricia L Fernandez; Thais Souto-Padron; María José De Rosa; Michelle Kelliher; Douglas Golenbock; Francis K M Chan; Marcelo T Bozza |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-18 |
Journal Detail:
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Title: Blood Volume: - ISSN: 1528-0020 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-20 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Instituto de Microbiologia Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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