A key role for CC chemokine receptor 4 in lipopolysaccharide-induced endotoxic shock.
CC chemokine receptor (CCR)4, a high affinity receptor for the CC chemokines thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC), is expressed in the thymus and spleen, and also by peripheral blood T cells, macrophages, platelets, and basophils. Recent studies have shown that CCR4 is the major chemokine receptor expressed by T helper type 2 (Th2) polarized cells. To study the in vivo role of CCR4, we have generated CCR4-deficient (CCR4(-/-)) mice by gene targeting. CCR4(-/-) mice developed normally. Splenocytes and thymocytes isolated from the CCR4(-/-) mice failed to respond to the CCR4 ligands TARC and MDC, as expected, but also surprisingly did not undergo chemotaxis in vitro in response to macrophage inflammatory protein (MIP)-1alpha. The CCR4 deletion had no effect on Th2 differentiation in vitro or in a Th2-dependent model of allergic airway inflammation. However, CCR4(-/-) mice exhibited significantly decreased mortality on administration of high or low dose bacterial lipopolysaccharide (LPS) compared with CCR4(+/+) mice. After high dose LPS treatment, serum levels of tumor necrosis factor alpha, interleukin 1beta, and MIP-1alpha were reduced in CCR4(-/-) mice, and decreased expression of MDC and MIP-2 mRNA was detected in peritoneal exudate cells. Analysis of peritoneal lavage cells from CCR4(-/)- mice by flow cytometry also revealed a significant decrease in the F4/80(+) cell population. This may reflect a defect in the ability of the CCR4(-/-) macrophages to be retained in the peritoneal cavity. Taken together, our data reveal an unexpected role for CCR4 in the inflammatory response leading to LPS-induced lethality.
Chvatchko
Y
Y
Serono Pharmaceutical Research Institute, 1228 Plan-les-Ouates/Geneva, Switzerland. yolande.chvatchko@serono.com
Hoogewerf
A J
AJ
Meyer
A
A
Alouani
S
S
Juillard
P
P
Buser
R
R
Conquet
F
F
Proudfoot
A E
AE
Wells
T N
TN
Power
C A
CA
D000818:Animals; D001483:Base Sequence; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D019742:Chemokines, CC / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D054398:Receptors, CCR4; D019707:Receptors, Chemokine / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012772:Shock, Septic / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D013601:T-Lymphocytes / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology
C499538:Ccl17 protein, mouse; C515483:Ccl22 protein, mouse; C515355:Ccr4 protein, mouse; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D019742:Chemokines, CC; D017931:DNA Primers; D008070:Lipopolysaccharides; D054398:Receptors, CCR4; D019707:Receptors, Chemokine