CX3CR1 modulates the anti-inflammatory activity of hepatic dendritic cells in response to acute liver injury.

The chemokine fractalkine (CX3CL1) and its receptor CX3CR1 are known to mediate leukocyte chemotaxis, adhesion and survival. In the liver, CX3CR1 is expressed on multiple cell types including monocytes and dendritic cells. However, the function of CX3CR1 on hepatic dendritic cells (HDCs) is still poorly understood. In this study, we investigated the role of CX3CR1 on mouse HDCs during homeostasis and following acute liver injury. At homeostasis, CX3CR1-expression was detected among CD11b+/CD103- type 2 myeloid HDCs (mHDCs) and these cells were characterized by the production of IL-10.   Mice treatment with the hepatotoxic agent CCl4 up-regulated liver IL-10 expression and stimulated the expansion of CX3CR1+ mHDCs which also showed a more mature phenotype. The absence of CX3CR1 in naïve CX3CR1gfp/gfp mice specifically reduced the CD11b+/IL-10+ mHDCs as compared to CX3CR1-proficient animals (CX3CR1+/gfp).  Following CCl4 poisoning, the liver recruitment and maturation of CD11b+ mHDCs was significantly attenuated in CX3CR1gfp/gfp mice. Furthermore, these mice suffered more severe hepatic injury and inflammation than CX3CR1+/gfp mice and showed a delated recovery from liver damage. Such a worsening of liver injury in CX3CR1gfp/gfp mice was associated with an impaired up-regulation of hepatic IL-10 expression and a lower number of IL-10 producing CD11b+ mHDCs. Consistently, IL-10 inactivation enhanced hepatic injury and inflammation in CX3CR1+/gfp mice receiving CCl4 Altogether, these data indicate a novel role of the CX3CL1/CX3CR1 axis in liver type 2 mHDC functions, pointing out the importance of CX3CR1 in promoting IL-10-mediated anti-inflammatory actions of HDCs. ©2017 The Author(s).