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

The chemokine fractalkine (C–X3–C motif chemokine ligand 1, CX₃CL1) and its receptor (C–X3–C motif chemokine receptor 1, 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 the present study, we investigated the role of CX₃CR1 on mouse HDCs during homeostasis and following acute liver injury. At homeostasis, CX₃CR1 expression was detected amongst CD11b⁺/CD103⁻ type 2 myeloid HDCs (mHDCs) and these cells were characterized by the production of interleukin-10 (IL-10). Mice treatment with the hepatotoxic agent carbon tetrachloride (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 CX₃CR1^gfp/gfp mice specifically reduced the CD11b⁺/IL-10⁺ mHDCs as compared with CX₃CR1-proficient animals (CX₃CR1^+/gfp). Following CCl₄ poisoning, the liver recruitment and maturation of CD11b⁺ mHDCs was significantly attenuated in CX₃CR1^gfp/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 CX₃CR1^gfp/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.