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Impaired hepatic granuloma formation in mice deficient in C–C chemokine receptor 2
Author(s) -
Jinnouchi Katsunori,
Terasaki Yasuhiro,
Fujiyama Shigetoshi,
Tomita Kimio,
Kuziel William A,
Maeda Nobuyo,
Takahashi Kiyoshi,
Takeya Motohiro
Publication year - 2003
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.1362
Subject(s) - ccr2 , chemokine , granuloma , cytokine , epithelioid cell , biology , chemokine receptor , giant cell , pathology , immunology , immunohistochemistry , inflammation , medicine
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‐γ in CCR2−/− mice. These data clearly indicate that signalling through CCR2 has many effects on the normal growth and development of hepatic granulomas. Copyright © 2003 John Wiley & Sons, Ltd.