CCR5 deficiency drives enhanced natural killer cell trafficking to and activation within the liver in murine T cell-mediated hepatitis.
Natural killer (NK) cells are innate immune cells that are enriched in the liver, but the processes underlying NK cell trafficking to the liver and cellular activation within the liver of patients with T cell-mediated liver diseases remain poorly defined. Concanavalin A (Con A) hepatitis is a murine model mimicking many aspects of human T cell-mediated liver diseases. Here we demonstrate that severe hepatitis in CCR5-deficient (KO) mice is associated with increased hepatic NK cell recruitment driven by enhanced hepatic production of CCL5 acting via CCR1 and by enhanced hepatic NK cell activation relative to that observed in wild-type mice after Con A administration. Furthermore, NK cell depletion ameliorated severe hepatitis in CCR5 KO mice but did not alter hepatitis in wild-type mice after Con A treatment. We propose that in the setting of CCR5 deficiency NK cells assume a profound effector role in Con A hepatitis via enhanced CCL5-CCR1 driven hepatic recruitment in addition to augmented cytokine-driven NK cell activation to produce interferon-gamma. These results highlight the potential profound impact of altered chemokine receptor expression on the innate immune response in the setting of T cell-mediated hepatitis.
Ajuebor
Maureen N
MN
Department of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada.
Wondimu
Zenebech
Z
Hogaboam
Cory M
CM
Le
Tai
T
Proudfoot
Amanda E I
AE
Swain
Mark G
MG
D000818:Animals; D065100:CCR5 Receptor Antagonists; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000276:immunology; D003208:Concanavalin A / Q000494:pharmacology*; D004195:Disease Models, Animal; D006505:Hepatitis / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D054389:Receptors, CCR1; D019713:Receptors, CCR5 / Q000172:deficiency* / Q000276:immunology; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000276:immunology; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000276:immunology*
C515300:CCR1 protein, human; D065100:CCR5 Receptor Antagonists; C515301:Ccr1 protein, mouse; D018946:Chemokine CCL5; C108335:RANTES, Met-; D054389:Receptors, CCR1; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D003208:Concanavalin A; D015847:Interleukin-4; D007371:Interferon-gamma