CD11b+Gr1+bone marrow cells ameliorate liver fibrosis by producing interleukin-10 in mice
Open Access
- 27 April 2012
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Hepatology
- Vol. 56 (5), 1902-1912
- https://doi.org/10.1002/hep.25817
Abstract
Clinical trials and animal models suggest that infusion of bone marrow cells (BMCs) is effective therapy for liver fibrosis, but the underlying mechanisms are obscure, especially those associated with early effects of BMCs. Here, we analyzed the early impact of BMC infusion and identified the subsets of BMCs showing antifibrotic effects in mice with carbon tetrachloride–induced liver fibrosis. An interaction between BMCs and activated hepatic stellate cells (HSCs) was investigated using an in vitro coculturing system. Within 24 hours, infused BMCs were in close contact with activated HSCs, which was associated with reduced liver fibrosis, enhanced hepatic expression of interleukin (IL)-10, and expanded regulatory T cells but decreased macrophage infiltration in the liver at 24 hours after BMC infusion. In contrast, IL-10–deficient (IL-10−/−) BMCs failed to reproduce these effects in fibrotic livers. Intriguingly, in isolated cells, CD11b+Gr1highF4/80− and CD11b+Gr1+F4/80+ BMCs expressed more IL-10 after coculturing with activated HSCs, leading to suppressed expression of collagen and α-smooth muscle actin in HSCs. Moreover, these effects were either enhanced or abrogated, respectively, when BMCs were cocultured with IL-6−/− and retinaldehyde dehydrogenase 1−/− HSCs. Similar to murine data, human BMCs expressed more IL-10 after coculturing with human HSC lines (LX-2 or hTERT), and serum IL-10 levels were significantly elevated in patients with liver cirrhosis after autologous BMC infusion. Conclusion: Activated HSCs increase IL-10 expression in BMCs (CD11b+Gr1highF4/80− and CD11b+Gr1+F4/80+ cells), which in turn ameliorates liver fibrosis. Our findings could enhance the design of BMC therapy for liver fibrosis. (HEPATOLOGY 2012;56:1902–1912)This publication has 33 references indexed in Scilit:
- Dendritic cell regulation of carbon tetrachloride-induced murine liver fibrosis regressionHepatology, 2011
- Hepatic Stellate Cells Function as Regulatory BystandersThe Journal of Immunology, 2011
- Tumor development in murine ulcerative colitis depends on MyD88 signaling of colonic F4/80+CD11bhighGr1low macrophagesJCI Insight, 2011
- Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration, and functionHepatology, 2011
- Pathogenesis of Liver FibrosisAnnual Review Of Pathology-Mechanisms Of Disease, 2011
- CCR2 mediates hematopoietic stem and progenitor cell trafficking to sites of inflammation in miceJCI Insight, 2010
- An In Vivo Model for Monitoring Trans-Differentiation of Bone Marrow Cells into Functional HepatocytesThe Journal of Biochemistry, 2003
- All-trans-retinoic acid eliminates immature myeloid cells from tumor-bearing mice and improves the effect of vaccination.2003
- Mechanism of Immune Dysfunction in Cancer Mediated by Immature Gr-1+ Myeloid CellsThe Journal of Immunology, 2001
- Interleukin-10 and the Interleukin-10 ReceptorAnnual Review of Immunology, 2001