Absence of CC chemokine receptor 8 enhances innate immunity during septic peritonitis.
An effective clearance of microbes is crucial in host defense during infection. In the present study, we demonstrate that CC chemokine receptor 8 (CCR8) skews innate immune response during septic peritonitis induced by cecal ligation and puncture (CLP). CCR8 was expressed in resident peritoneal macrophages and elicited leukocytes during CLP in the wild-type CCR8+/+ mice. CCR8-/- mice were resistant to CLP-induced lethality relative to CCR8+/+ mice, and this resistance was associated with an augmented bacterial clearance in CCR8-/- mice. In vitro, peritoneal macrophages from CCR8-/- mice, but not neutrophils, exhibited enhanced bactericidal activities relative to those from CCR8+/+ mice. Upon stimulation with the bacterial component LPS, elevated levels of superoxide generation, lysosomal enzyme release, and nitric oxide generation, effector molecules for bacterial killing were detected in CCR8-/- macrophages relative to CCR8+/+ macrophages. In addition, CCR8-/- macrophages produced significantly higher levels than CCR8+/+ macrophages of several cytokines and chemokines known to augment bactericidal activities of leukocytes that include TNF-alpha, IL-12, macrophage-derived chemokine (MDC/CCL22), macrophage inflammatory protein (MIP)-2, and KC. Altogether, these results indicate that CCR8 may have a negative impact on host defense during septic peritonitis, providing a new paradigm for the role of CCR8 in innate immunity.
Matsukawa
Akihiro
A
Department of Pathology and Experimental Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. matsu@kaiju.medic.kumamoto-u.ac.jp
Kudoh
Shinji
S
Sano
Gen-ichiro
G
Maeda
Takako
T
Ito
Takaaki
T
Lukacs
Nicholas W
NW
Hogaboam
Cory M
CM
Kunkel
Steven L
SL
Lira
Sergio A
SA
D000818:Animals; D001424:Bacterial Infections / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000172:deficiency* / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D007113:Immunity, Innate / Q000276:immunology*; D007668:Kidney / Q000293:injuries / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D010538:Peritonitis / Q000276:immunology*; D010587:Phagocytosis; D054401:Receptors, CCR8
C489319:Ccr8 protein, mouse; D016207:Cytokines; D054401:Receptors, CCR8