title: Serum amyloid A chemoattracts immature dendritic cells and indirectly provokes monocyte chemotaxis by induction of cooperating CC and CXC chemokines.
abstract: Serum amyloid A (SAA) is an acute phase protein that is upregulated in inflammatory diseases and chemoattracts monocytes, lymphocytes, and granulocytes via its G protein-coupled receptor formyl peptide receptor like 1/formyl peptide receptor 2 (FPRL1/FPR2). Here, we demonstrated that the SAA1α isoform also chemoattracts monocyte-derived immature dendritic cells (DCs) in the Boyden and μ-slide chemotaxis assay and that its chemotactic activity for monocytes and DCs was indirectly mediated via rapid chemokine induction. Indeed, SAA1 induced significant amounts (≥5 ng/mL) of macrophage inflammatory protein-1α/CC chemokine ligand 3 (MIP-1α/CCL3) and interleukin-8/CXC chemokine ligand 8 (IL-8/CXCL8) in monocytes and DCs in a dose-dependent manner within 3 h. However, SAA1 also directly activated monocytes and DCs for signaling and chemotaxis without chemokine interference. SAA1-induced monocyte migration was nevertheless significantly prevented (60-80% inhibition) in the constant presence of desensitizing exogenous MIP-1α/CCL3, neutralizing anti-MIP-1α/CCL3 antibody, or a combination of CC chemokine receptor 1 (CCR1) and CCR5 antagonists, indicating that this endogenously produced CC chemokine was indirectly contributing to SAA1-mediated chemotaxis. Further, anti-IL-8/CXCL8 antibody neutralized SAA1-induced monocyte migration, suggesting that endogenous IL-8/CXCL8 acted in concert with MIP-1α/CCL3. This explained why SAA1 failed to synergize with exogenously added MIP-1α/CCL3 or stromal cell-derived factor-1α (SDF-1α)/CXCL12 in monocyte and DC chemotaxis. In addition to direct leukocyte activation, SAA1 induces a chemotactic cascade mediated by expression of cooperating chemokines to prolong leukocyte recruitment to the inflammatory site.
authors.affiliation: Laboratory of Molecular Immunology, Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.
authors.forename: Mieke
authors.initials: M
authors.lastname: Gouwy
authors.forename: Mieke
authors.initials: M
authors.lastname: De Buck
authors.forename: Noëmie
authors.initials: N
authors.lastname: Pörtner
authors.forename: Ghislain
authors.initials: G
authors.lastname: Opdenakker
authors.forename: Paul
authors.initials: P
authors.lastname: Proost
authors.forename: Sofie
authors.initials: S
authors.lastname: Struyf
authors.forename: Jo
authors.initials: J
authors.lastname: Van Damme
mesh_terms: D057134:Antibodies, Neutralizing / Q000494:pharmacology; D002460:Cell Line; D054405:Chemokine CCL3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D054377:Chemokine CXCL12 / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D015194:Diffusion Chambers, Culture; D004306:Dose-Response Relationship, Immunologic; D005786:Gene Expression Regulation; D006801:Humans; D016209:Interleukin-8 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D061251:Primary Cell Culture; D054389:Receptors, CCR1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D019713:Receptors, CCR5 / Q000235:genetics / Q000276:immunology; D011994:Recombinant Proteins / Q000494:pharmacology; D000685:Serum Amyloid A Protein / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: D057134:Antibodies, Neutralizing; C515429:CCL3 protein, human; C515300:CCR1 protein, human; C584933:CCR5 protein, human; C515255:CXCL12 protein, human; D054405:Chemokine CCL3; D054377:Chemokine CXCL12; D016209:Interleukin-8; D054389:Receptors, CCR1; D019713:Receptors, CCR5; D011994:Recombinant Proteins; C521404:SAA1 protein, human; D000685:Serum Amyloid A Protein
keywords: Chemokines; Chemotaxis; DCs; Monocytes; Serum amyloid A