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| [PMID]: | 28733463 |
| [Au] Autor: | Zaal A; Nota B; Moore KS; Dieker M; van Ham SM; Ten Brinke A |
| [Ad] Endereço: | Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. |
| [Ti] Título: | TLR4 and C5aR crosstalk in dendritic cells induces a core regulatory network of RSK2, PI3Kß, SGK1, and FOXO transcription factors. |
| [So] Source: | J Leukoc Biol;102(4):1035-1054, 2017 Oct. | | [Is] ISSN: | 1938-3673 |
| [Cp] País de publicação: | United States |
| [La] Idioma: | eng |
| [Ab] Resumo: | Crosstalk between complement component 5a receptors (C5aRs) and TLRs in dendritic cells (DCs) occurs upon pathogen invasion; however, studies on C5aR and TLR crosstalk mainly focused on the modulating effect of C5a on TLR-induced cytokine production. To elucidate the breadth of C5aR and TLR4 crosstalk, the effect of simultaneous treatment with C5a and LPS was investigated in human monocyte-derived DCs (moDCs) 2 h after stimulation using whole transcriptome sequencing analysis. Although the effect of C5a on hallmark genes defining TLR4-induced DC maturation was limited at this time point, RNA sequencing analysis revealed a great variety of novel C5a targets, of which many interfere with TLR4-mediated immune activation. Analysis of functional relationships among these genes uncovered induction of a central immune regulatory network upon C5aR and TLR4 crosstalk, involving the transcription factors forkhead box (FOX)O1 and FOXO3 and the signaling molecules serum- and glucocorticoid-inducible kinase (SGK1), ribosomal S6 kinase 2 (RSK2), and PI3Kß. C5aR and TLR crosstalk, furthermore, yielded down-regulation of mainly proinflammatory network branches, including IL-12B, IL-2Rα (IL-2RA), and jagged 1 (JAG1) and cooperative induction of predominantly anti-inflammatory network branches, including sphingosine kinase 1 (SPHK1), ß2 adrenergic receptor (ADRB2), gastric inhibitory polypeptide receptor (GIPR), and four-and-a-half Lin11, Isl-1, and Mec-3 domains protein 2 (FHL2). Together, these data point toward induction of generalized immune regulation of DC function. Motif enrichment analysis indicate a prominent role for basic leucine zipper (bZIP) and IFN regulatory factor 4 (IRF4) transcription factors upon C5aR and TLR4 crosstalk. Additionally, differences were observed in the modulating capacity of C5a on DCs in the absence or presence of a pathogen (TLR stimulus). Our findings shed new light on the depth and complexity of C5aR and TLR4 crosstalk and provide new foci of research for future studies. |
| [Mh] Termos MeSH primário: |
Células Dendríticas/imunologia
Proteína Forkhead Box O1/imunologia
Proteína Forkhead Box O3/imunologia
Proteínas Imediatamente Precoces/imunologia
Fosfatidilinositol 3-Quinases/imunologia
Proteínas Serina-Treonina Quinases/imunologia
Receptor da Anafilatoxina C5a/imunologia
Proteínas Quinases S6 Ribossômicas 90-kDa/imunologia
Transdução de Sinais/imunologia
Receptor 4 Toll-Like/imunologia
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| [Mh] Termos MeSH secundário: |
Seres Humanos
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| [Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (C5AR1 protein, human); 0 (FOXO1 protein, human); 0 (FOXO3 protein, human); 0 (Forkhead Box Protein O1); 0 (Forkhead Box Protein O3); 0 (Immediate-Early Proteins); 0 (Receptor, Anaphylatoxin C5a); 0 (TLR4 protein, human); 0 (Toll-Like Receptor 4); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 90-kDa); EC 2.7.11.1 (ribosomal protein S6 kinase, 90kDa, polypeptide 3); EC 2.7.11.1 (serum-glucocorticoid regulated kinase) |
| [Em] Mês de entrada: | 1710 |
| [Cu] Atualização por classe: | 171009 |
[Lr] Data última revisão:
| 171009 |
| [Sb] Subgrupo de revista: | IM |
| [Da] Data de entrada para processamento: | 170723 |
| [St] Status: | MEDLINE |
| [do] DOI: | 10.1189/jlb.2MA0217-058R |
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