Ccl2 and Ccl3 mediate neutrophil recruitment via induction of protein synthesis and generation of lipid mediators.
OBJECTIVE
Although the chemokines monocyte chemoattractant protein-1 (Ccl2/JE/MCP-1) and macrophage inflammatory protein-1alpha (Ccl3/MIP-1alpha) have recently been implicated in neutrophil migration, the underlying mechanisms remain largely unclear.


RESULTS
Stimulation of the mouse cremaster muscle with Ccl2/JE/MCP-1 or Ccl3/MIP-1alpha induced a significant increase in numbers of firmly adherent and transmigrated leukocytes (>70% neutrophils) as observed by in vivo microscopy. This increase was significantly attenuated in mice receiving an inhibitor of RNA transcription (actinomycin D) or antagonists of platelet activating factor (PAF; BN 52021) and leukotrienes (MK-886; AA-861). In contrast, leukocyte responses elicited by PAF and leukotriene-B(4) (LTB(4)) themselves were not affected by actinomycin D, BN 52021, MK-886, or AA-861. Conversely, PAF and LTB(4), but not Ccl2/JE/MCP-1 and Ccl3/MIP-1alpha, directly activated neutrophils as indicated by shedding of CD62L and marked upregulation of CD11b. Moreover, Ccl2/JE/MCP-1- and Ccl3/MIP-1alpha-elicited leakage of fluorescein isothiocyanate dextran as well as collagen IV remodeling within the venular basement membrane were completely absent in neutrophil-depleted mice.


CONCLUSIONS
Ccl2/JE/MCP-1 and Ccl3/MIP-1alpha mediate firm adherence and (subsequent) transmigration of neutrophils via protein synthesis and secondary generation of leukotrienes and PAF, which in turn directly activate neutrophils. Thereby, neutrophils facilitate basement membrane remodeling and promote microvascular leakage.
Reichel
Christoph Andreas
CA
Walter Brendel Centre of Experimental Medicine, Munich, Germany. christoph.reichel@med.uni-muenchen.de
Rehberg
Markus
M
Lerchenberger
Max
M
Berberich
Nina
N
Bihari
Peter
P
Khandoga
Alexander Georg
AG
Zahler
Stefan
S
Krombach
Fritz
F
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000494:pharmacology; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism* / Q000494:pharmacology; D054405:Chemokine CCL3 / Q000378:metabolism* / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology; D003609:Dactinomycin / Q000494:pharmacology; D004195:Disease Models, Animal; D007211:Indoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007975:Leukotriene B4 / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000502:physiology*; D014176:Protein Biosynthesis / Q000187:drug effects*; D011897:Random Allocation; D012680:Sensitivity and Specificity; D002722:Chlorobenzenes
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D016227:Benzoquinones; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D003609:Dactinomycin; D007211:Indoles; D007213:Indomethacin; D007975:Leukotriene B4; D016859:Lipoxygenase Inhibitors; C060893:MK-886; D002722:Chlorobenzenes; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone