Abstract
Recent evidence suggests that hepatic dendritic cells (HDCs) contribute to the evolution of chronic liver diseases. However, the HDC subsets involved and the mechanisms driving these responses are still poorly understood. In this study, we have investigated the role of the fractalkine receptor CX3CR1 in modulating monocyte-derived dendritic cell (moDC) differentiation during liver inflammation. The phenotype of HDC and functional relevance of CX3CR1 was assessed in mice following necro-inflammatory liver injury induced by the hepatotoxic agent carbon tetrachloride (CCl4) and in steatohepatitis caused by a methionine/choline-deficient (MCD) diet. In both the experimental models, hepatic inflammation was associated with a massive expansion of CD11c+/MHCIIhigh/CD11b+ myeloid HDCs. These cells also expressed the monocyte markers Ly6C, chemokine (C-C Motif) receptor 2 (CCR2), F4/80 and CD88, along with CX3CR1, allowing their tentative identification as moDCs. Mice defective in CX3CR1 showed a reduction in liver-moDC recruitment following CCl4 poisoning in parallel with a defective maturation of monocytes into moDCs. The lack of CX3CR1 also affected moDC differentiation from bone marrow myeloid cells induced by granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-4 (IL-4) in vitro. In wild-type mice, treatment with the CX3CR1 antagonist CX3-AT (150 µg, i.p.) 24 h after CCl4 administration reduced liver moDCS and significantly ameliorated hepatic injury and inflammation. Altogether, these results highlight the possible involvement of moDCs in promoting hepatic inflammation following liver injury and indicated a novel role of CX3CL1/CX3CR1 dyad in driving the differentiation of hepatic moDCs.
Highlights
In recent years, growing attention has been paid to the importance of myeloid cells in modulating the evolution of both acute and chronic liver injury [1,2]
We have reported that type-2 myeloid hepatic dendritic cells (HDCs) expressing the fractalkine receptor CX3 CR1 and producing IL-10 are present in the liver during homeostasis and counteract acute hepatic inflammation [16], while the subsequent chronic liver injury HDCs featuring
They differed from CX3 CR1low type-2 myeloid HDCs present at homeostasis [4,16] by featuring the monocyte/macrophage markers Ly6C and F4-80 along with chemokine (C-C Motif) receptor 2 (CCR2), the receptor of the monocyte-recruiting chemokines CCL2/CCL7 (Figure 2A)
Summary
In recent years, growing attention has been paid to the importance of myeloid cells in modulating the evolution of both acute and chronic liver injury [1,2]. HDCs are mainly localized in the portal areas, a recent study in mice has identified them under the liver capsule [5]. HDCs display a predominant immature phenotype characterized by a low capacity to endocytose antigens and stimulate T-lymphocytes. These features, along with the production of interleukin-10
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
