C-C motif chemokine CCL3 and canonical neutrophil attractants promote neutrophil extravasation through common and distinct mechanisms.
Initial observations suggested that C-C motif chemokines exclusively mediate chemotaxis of mononuclear cells. In addition, recent studies also implicated these chemotactic cytokines in the recruitment of neutrophils. The underlying mechanisms remained largely unknown. Using in vivo microscopy on the mouse cremaster muscle, intravascular adherence and subsequent paracellular transmigration of neutrophils elicited by the chemokine (C-C motif) ligand 3 (CCL3, synonym MIP-1α) were significantly diminished in mice with a deficiency of the chemokine (C-C motif) receptor 1 (Ccr1(-/-)) or 5 (Ccr5(-/-)). Using cell-transfer techniques, neutrophil responses required leukocyte CCR1 and nonleukocyte CCR5. Furthermore, neutrophil extravasation elicited by CCL3 was almost completely abolished on inhibition of G protein-receptor coupling and PI3Kγ-dependent signaling, while neutrophil recruitment induced by the canonical neutrophil attractants chemokine (C-X-C motif) ligand 1 (CXCL1, synonym KC) or the lipid mediator platetelet-activating factor (PAF) was only partially reduced. Moreover, Ab blockade of β(2) integrins, of α(4) integrins, or of their putative counter receptors ICAM-1 and VCAM-1 significantly attenuated CCL3-, CXCL1-, or PAF-elicited intravascular adherence and paracellular transmigration of neutrophils. These data indicate that the C-C motif chemokine CCL3 and canonical neutrophil attractants exhibit both common and distinct mechanisms for the regulation of intravascular adherence and transmigration of neutrophils.
Klinikum der Universität München, Walter Brendel Centre of Experimental Medicine, Campus Grosshadern, Ludwig-Maximilians-Universität München, Marchioninistrasse 15, Munich, Germany. christoph.reichel@med.uni-muenchen.de
Christoph A
CA
Reichel
Daniel
D
Puhr-Westerheide
Gabriele
G
Zuchtriegel
Bernd
B
Uhl
Nina
N
Berberich
Stefan
S
Zahler
Matthias P
MP
Wymann
Bruno
B
Luckow
Fritz
F
Krombach
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000502:physiology; D054405:Chemokine CCL3 / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D016023:Integrins / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism*; D054389:Receptors, CCR1 / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D002352:Carrier Proteins; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D016023:Integrins; C561966:PAF protein, mouse; D054389:Receptors, CCR1; D019713:Receptors, CCR5; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1