title: Impaired hepatic granuloma formation in mice deficient in C-C chemokine receptor 2.
abstract: Granulomas are characterized histologically by a nodular collection of macrophages with occasional admixture of epithelioid cells, multinucleate giant cells, and other immunocompetent cells. Chemokines are considered to play an important role in the recruitment of these constituent cells of granulomas. The present study has examined the effect of a deficiency of C-C chemokine receptor-2 (CCR2) on hepatic granuloma formation induced by a single injection of Zymosan A. In CCR2+/+ mice, the number and the size of granulomas gradually increased until they reached peak values at 10 days after the injection. In contrast, both the number and the size of granulomas were smaller in CCR2-/- mice than in CCR2+/+ mice from days 5 to 21. They showed low peaks at day 5, after which the number and the size of the granulomas gradually decreased. Immunohistochemical analysis of the constituent granuloma cells using cell type-specific monoclonal antibodies revealed rapid accumulation of blood monocytes, with subsequent differentiation to macrophages, in CCR2+/+ mice during days 2-10. This process was greatly impaired in CCR2-/- mice and granulomas remained small. At all time points, the percentage of polymorphonuclear cells in granulomas was higher in CCR2-/- mice than in CCR2+/+ mice. Interestingly, multinucleate giant cells were frequently observed in granulomas in CCR2-/- mice, whereas they rarely appeared in CCR2+/+ mice. Profiles of liver cytokine RNA levels as well as serum cytokine levels revealed reduced expression of the Th1 cytokine IFN-gamma in CCR2-/- mice. These data clearly indicate that signalling through CCR2 has many effects on the normal growth and development of hepatic granulomas.
authors.affiliation: Second Department of Pathology, Kumamoto University School of Medicine, 2-2-1 Honjo, Kumamoto 862-0811, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Jinnouchi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Terasaki
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Fujiyama
authors.forename: Kimio
authors.initials: K
authors.lastname: Tomita
authors.forename: William A
authors.initials: WA
authors.lastname: Kuziel
authors.forename: Nobuyo
authors.initials: N
authors.lastname: Maeda
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takahashi
authors.forename: Motohiro
authors.initials: M
authors.lastname: Takeya
mesh_terms: D000818:Animals; D016207:Cytokines / Q000032:analysis; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006099:Granuloma / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry / Q000379:methods; D007371:Interferon-gamma / Q000032:analysis; D008107:Liver Diseases / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron / Q000379:methods; D009000:Monocytes / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000172:deficiency*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: C515335:Ccr2 protein, mouse; D016207:Cytokines; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma