Impaired hepatic granuloma formation in mice deficient in C-C chemokine receptor 2
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Published on: March 24, 2015
Katsunori Jinnouchi1, Yasuhiro Terasaki, Shigetoshi Fujiyama
1Second Department of Pathology, Kumamoto University School of Medicine, 2-2-1 Honjo, Kumamoto 862-0811, Japan.
Insights
Mice lacking C-C chemokine receptor-2 (CCR2) showed impaired hepatic granuloma formation. CCR2 signaling is crucial for the normal development and cellular recruitment in granulomas.
Area of Science:
- Immunology
- Cell Biology
- Pathology
Background:
- Granulomas are collections of macrophages and other immune cells.
- Chemokines mediate the recruitment of cells to form granulomas.
Purpose of the Study:
- To investigate the role of C-C chemokine receptor-2 (CCR2) in hepatic granuloma formation.
- To understand the impact of CCR2 deficiency on granuloma development and cellular composition.
Main Methods:
- Hepatic granuloma formation was induced by Zymosan A injection in wild-type (CCR2+/+) and CCR2-deficient (CCR2-/-) mice.
- Granuloma size and cell counts were analyzed over time.
- Immunohistochemistry was used to identify cell types within granulomas.
- Cytokine RNA and serum levels were measured.
Main Results:
- CCR2 deficiency significantly reduced the number and size of hepatic granulomas.
- Monocyte recruitment and differentiation into macrophages were impaired in CCR2-/- mice.
- CCR2-/- mice exhibited increased polymorphonuclear cells and multinucleate giant cells within granulomas.
- Reduced expression of the Th1 cytokine IFN-gamma was observed in CCR2-/- mice.
Conclusions:
- Signaling through CCR2 is essential for the normal growth and development of hepatic granulomas.
- CCR2 plays a critical role in monocyte recruitment and macrophage differentiation during granuloma formation.
- CCR2 deficiency alters the cellular composition and cytokine profile of granulomas.
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.
