Abstract:
:TLR and complement activation ensures efficient clearance of infection. Previous studies documented synergism between TLRs and the receptor for the pro-inflammatory complement peptide C5a (C5aR/CD88), and regulation of TLR-induced pro-inflammatory responses by C5aR, suggesting crosstalk between TLRs and C5aR. However, it is unclear whether and how TLRs modulate C5a-induced pro-inflammatory responses. We demonstrate a marked positive modulatory effect of TLR activation on cell sensitivity to C5a in vitro and ex vivo and identify an underlying mechanistic target. Pre-exposure of PBMCs and whole blood to diverse TLR ligands or bacteria enhanced C5a-induced pro-inflammatory responses. This effect was not observed in TLR4 signalling-deficient mice. TLR-induced hypersensitivity to C5a did not result from C5aR upregulation or modulation of C5a-induced Ca(2+) mobilization. Rather, TLRs targeted another C5a receptor, C5L2 (acting as a negative modulator of C5aR), by reducing C5L2 activity. TLR-induced hypersensitivity to C5a was mimicked by blocking C5L2 and was not observed in C5L2KO mice. Furthermore, TLR activation inhibited C5L2 expression upon C5a stimulation. These findings identify a novel pathway of crosstalk within the innate immune system that amplifies innate host defense at the TLR-complement interface. Unravelling the mutually regulated activities of TLRs and complement may reveal new therapeutic avenues to control inflammation.
journal_name
Eur J Immunoljournal_title
European journal of immunologyauthors
Raby AC,Holst B,Davies J,Colmont C,Laumonnier Y,Coles B,Shah S,Hall J,Topley N,Köhl J,Morgan BP,Labéta MOdoi
10.1002/eji.201041350subject
Has Abstractpub_date
2011-09-01 00:00:00pages
2741-52issue
9eissn
0014-2980issn
1521-4141journal_volume
41pub_type
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journal_title:European journal of immunology
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journal_title:European journal of immunology
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journal_title:European journal of immunology
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journal_title:European journal of immunology
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journal_title:European journal of immunology
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abstract::Antigen-presenting macrophages (M phi) were derived from day 7 cultures of bone marrow stem cells using L cell conditioned medium. The adherent bone marrow-derived macrophages (BMM phi) were 100% esterase-positive, 95% positive for C3 receptors, 93% positive for Fc receptors, and 95% actively phagocytic. Indirect immu...
journal_title:European journal of immunology
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doi:10.1002/eji.1830121202
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journal_title:European journal of immunology
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doi:10.1002/eji.1830270726
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journal_title:European journal of immunology
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journal_title:European journal of immunology
pub_type: 杂志文章
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journal_title:European journal of immunology
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doi:10.1002/eji.1830091213
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journal_title:European journal of immunology
pub_type: 临床试验,杂志文章
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journal_title:European journal of immunology
pub_type: 杂志文章
doi:10.1002/eji.1830241118
更新日期:1994-11-01 00:00:00
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journal_title:European journal of immunology
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journal_title:European journal of immunology
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doi:10.1002/eji.1830110316
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journal_title:European journal of immunology
pub_type: 杂志文章
doi:10.1002/eji.1830110611
更新日期:1981-06-01 00:00:00
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journal_title:European journal of immunology
pub_type: 评论,杂志文章,评审
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更新日期:2007-01-01 00:00:00
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journal_title:European journal of immunology
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journal_title:European journal of immunology
pub_type: 杂志文章
doi:10.1002/eji.1830240828
更新日期:1994-08-01 00:00:00
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journal_title:European journal of immunology
pub_type: 杂志文章
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journal_title:European journal of immunology
pub_type: 杂志文章
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journal_title:European journal of immunology
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journal_title:European journal of immunology
pub_type: 杂志文章
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journal_title:European journal of immunology
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journal_title:European journal of immunology
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