Fibrinogen stimulates macrophage chemokine secretion through toll-like receptor 4.
Extravascular fibrin deposition is an early and persistent hallmark of inflammatory responses. Fibrin is generated from plasma-derived fibrinogen, which escapes the vasculature in response to endothelial cell retraction at sites of inflammation. Our ongoing efforts to define the physiologic functions of extravasated fibrin(ogen) have led to the discovery, reported here, that fibrinogen stimulates macrophage chemokine secretion. Differential mRNA expression analysis and RNase protection assays revealed that macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, MIP-2, and monocyte chemoattractant protein-1 are fibrinogen inducible in the RAW264.7 mouse macrophage-like cell line, and ELISA confirmed that both RAW264.7 cells and primary murine thioglycolate-elicited peritoneal macrophages up-regulate the secretion of monocyte chemoattractant protein-1 >100-fold upon exposure to fibrinogen. Human U937 and THP-1 precursor-1 (THP-1) monocytic cell lines also secreted chemokines in response to fibrinogen, upon activation with IFN-gamma and differentiation with vitamin D(3), respectively. LPS contamination could not account for our observations, as fibrinogen-induced chemokine secretion was sensitive to heat denaturation and was unaffected by the pharmacologic LPS antagonist polymyxin B. Nevertheless, fibrinogen- and LPS-induced chemokine secretion both apparently required expression of functional Toll-like receptor 4, as each was diminished in macrophages derived from C3H/HeJ mice. Thus, innate responses to fibrinogen and bacterial endotoxin may converge at the evolutionarily conserved Toll-like recognition molecules. Our data suggest that extravascular fibrin(ogen) induces macrophage chemokine expression, thereby promoting immune surveillance at sites of inflammation.
Smiley
S T
ST
Trudeau Institute, Saranac Lake, NY 12983, USA. ssmiley@trudeauinstitute.org
King
J A
JA
Hancock
W W
WW
D000818:Animals; D005075:Biological Evolution; D018821:CD18 Antigens / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D018925:Chemokines / Q000096:biosynthesis* / Q000235:genetics; D029721:Drosophila Proteins; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D016167:Integrin alphaXbeta2 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis / Q000235:genetics; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000187:drug effects* / Q000276:immunology*; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000187:drug effects* / Q000276:immunology*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D020298:U937 Cells
D018821:CD18 Antigens; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D029721:Drosophila Proteins; D016167:Integrin alphaXbeta2; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D016177:Macrophage-1 Antigen; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D005337:Fibrin; D005340:Fibrinogen