In contrast, mRNA levels of MIP-1β, which Selumetinib nmr binds to CCR5, and levels of the homeostatic chemokine, stromal cell-derived factor 1, were only slightly changed (Supporting Fig. 1C). We hypothesized that the

absence of CCR5 is responsible for macrophages’ failures to recruit to the damaged liver. To test this hypothesis, CFSC-labeled immune cells derived from WT, CCR1 KO, and CCR5 KO BM were adoptively transferred into both healthy WT and Mdr2-KO recipients. Forty-eight hours after transplantation, recipient WT mice displayed low levels of macrophage recruitment to the liver, independent of donor cell origin. In contrast, recipient Mdr2-KO mice showed increased liver recruitment of CFSE-positive cells when BM cells derived from WT or CCR1 KO were used. However, when BM cells were derived from CCR5 KO donors, this effect was abolished, with a 13-fold reduction in macrophage recruitment to the liver (Fig. 2D,E). Immunofluorescence staining for bile ducts in liver sections of adoptively transferred mice revealed that recruited CFSE-positive cells specifically

surround cholangiocytes (Fig. 2D). To further study the role of BM-derived macrophages in inflammation and fibrosis in livers of Mdr2-KO mice, 1-month-old Mdr2:CCR5 DKO mice underwent BM transplantation after lethal irradiation with donor BM cells derived from either WT Ku-0059436 order or CCR5−/− mice. At the age of 3 months, transplanted mice were sacrificed and liver inflammation and fibrosis was assessed. Accumulation of macrophages (F4-80 staining) and fibrosis (Sirius Red staining) were significantly increased in mice transplanted with WT BM cells, compared to mice receiving BM selleck chemical from CCR5−/− mice. These results further support the importance of CCR5 for trafficking and localization of BM-derived macrophages to the damaged liver (Supporting Fig. 2A). Ductolar reaction is thought to have a key role in

the initiation and progression of liver cirrhosis. Pan-CK staining for bile ducts in liver sections revealed extensive bile duct proliferation in livers of Mdr2-KO and Mdr2:CCR1 DKO mice, but not in Mdr2:CCR5 DKO livers (Fig. 3A). Mdr2:CCR5 DKO mice also had a 6-fold reduction in positively stained BrdU cells in the portal area, compared to both Mdr2-KO and Mdr2:CCR1 DKO mice (Fig. 3C and Supporting Fig. 2B). Therefore, it is suggested that periductal proliferation correlates with macrophage accumulation, and not liver damage, measured by enzyme levels. Oval cells, which are liver progenitor cells capable of differentiating into hepatocyte and bile duct epithelial cells, are located in the periductal area and were shown to proliferate around portal veins after liver damage.