title: Serum amyloid A1α induces paracrine IL-8/CXCL8 via TLR2 and directly synergizes with this chemokine via CXCR2 and formyl peptide receptor 2 to recruit neutrophils.
abstract: Cell migration depends on the ability of leukocytes to sense an external gradient of chemotactic proteins produced during inflammation. These proteins include chemokines, complement factors, and some acute phase proteins, such as serum amyloid A. Serum amyloid A chemoattracts neutrophils, monocytes, and T lymphocytes via its G protein-coupled receptor formyl peptide receptor 2. We demonstrate that serum amyloid A1α more potently chemoattracts neutrophils in vivo than in vitro. In contrast to CD14(+) monocytes, no rapid (within 2 h) induction of interleukin-8/CXC chemokine ligand 8 or macrophage-inflammatory protein-1α/CC chemokine ligand 3 was observed in purified human neutrophils after stimulation of the cells with serum amyloid A1α or lipopolysaccharide. Moreover, interleukin-8/CXC chemokine ligand 8 induction in monocytes by serum amyloid A1α was mediated by toll-like receptor 2 and was inhibited by association of serum amyloid A1α with high density lipoprotein. This indicates that the potent chemotactic response of neutrophils toward intraperitoneally injected serum amyloid A1α is indirectly enhanced by rapid induction of chemokines in peritoneal cells, synergizing in a paracrine manner with serum amyloid A1α. We observed direct synergy between IL-8/CXC chemokine ligand 8 and serum amyloid A1α, but not lipopolysaccharide, in chemotaxis and shape change assays with neutrophils. Furthermore, the selective CXC chemokine receptor 2 and formyl peptide receptor 2 antagonists, SB225002 and WRW4, respectively, blocked the synergy between IL-8/CXC chemokine ligand 8 and serum amyloid A1α in neutrophil chemotaxis in vitro, indicating that for synergy their corresponding G protein-coupled receptors are required. Additionally, SB225002 significantly inhibited serum amyloid A1α-mediated peritoneal neutrophil influx. Taken together, endogenous (e.g., IL-1β) and exogenous (e.g., lipopolysaccharide) inflammatory mediators induce primary chemoattractants such as serum amyloid A that synergize in an autocrine (monocyte) or a paracrine (neutrophil) fashion with secondary chemokines induced in stromal cells.
authors: *Laboratory of Molecular Immunology and Laboratory of Immunobiology, Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.
authors: Mieke
authors: M
authors: De Buck
authors: *Laboratory of Molecular Immunology and Laboratory of Immunobiology, Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.
authors: Nele
authors: N
authors: Berghmans
authors: *Laboratory of Molecular Immunology and Laboratory of Immunobiology, Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.
authors: Noëmie
authors: N
authors: Pörtner
authors: *Laboratory of Molecular Immunology and Laboratory of Immunobiology, Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.
authors: Lotte
authors: L
authors: Vanbrabant
authors: *Laboratory of Molecular Immunology and Laboratory of Immunobiology, Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.
authors: Maaike
authors: M
authors: Cockx
authors: *Laboratory of Molecular Immunology and Laboratory of Immunobiology, Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.
authors: Sofie
authors: S
authors: Struyf
authors: *Laboratory of Molecular Immunology and Laboratory of Immunobiology, Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.
authors: Ghislain
authors: G
authors: Opdenakker
authors: *Laboratory of Molecular Immunology and Laboratory of Immunobiology, Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.
authors: Paul
authors: P
authors: Proost
authors: *Laboratory of Molecular Immunology and Laboratory of Immunobiology, Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium jo.vandamme@rega.kuleuven.be.
authors: Jo
authors: J
authors: Van Damme
authors: *Laboratory of Molecular Immunology and Laboratory of Immunobiology, Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium.
authors: Mieke
authors: M
authors: Gouwy
mesh_terms: D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology*; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000276:immunology*; D008297:Male; D009504:Neutrophils / Q000276:immunology*; D019899:Paracrine Communication / Q000187:drug effects / Q000276:immunology*; D010671:Phenylurea Compounds / Q000494:pharmacology; D044042:Receptors, Formyl Peptide / Q000276:immunology*; D023063:Receptors, Interleukin-8B / Q000276:immunology*; D044067:Receptors, Lipoxin / Q000276:immunology*; D000685:Serum Amyloid A Protein / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000276:immunology*
chemical_list: C508606:CXCL8 protein, human; C105101:FPR2 protein, human; D016209:Interleukin-8; D010671:Phenylurea Compounds; D044042:Receptors, Formyl Peptide; D023063:Receptors, Interleukin-8B; D044067:Receptors, Lipoxin; C112019:SB 225002; D000685:Serum Amyloid A Protein; C495342:TLR2 protein, human; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; C481578:formyl peptide receptor 2, mouse
keywords: G protein-coupled receptor; chemoattractants; chemotaxis