CXCR1 modulates the anti-inflammatory activity of hepatic dendritic cells in response to acute liver injury.

The chemokine fractalkine (CXCL1) and its receptor CXCR1 are known to mediate leukocyte chemotaxis, adhesion and survival. In the liver, CXCR1 is expressed on multiple cell types including monocytes and dendritic cells. However, the function of CXCR1 on hepatic dendritic cells (HDCs) is still poorly understood. In this study, we investigated the role of CXCR1 on mouse HDCs during homeostasis and following acute liver injury. At homeostasis, CXCR1-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 CCl up-regulated liver IL-10 expression and stimulated the expansion of CXCR1 mHDCs which also showed a more mature phenotype. The absence of CXCR1 in naïve CXCR1 mice specifically reduced the CD11b/IL-10 mHDCs as compared to CXCR1-proficient animals (CXCR1).  Following CCl poisoning, the liver recruitment and maturation of CD11b mHDCs was significantly attenuated in CXCR1 mice. Furthermore, these mice suffered more severe hepatic injury and inflammation than CXCR1 mice and showed a delated recovery from liver damage. Such a worsening of liver injury in CXCR1 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 mice receiving CCl Altogether, these data indicate a novel role of the CXCL1/CXCR1 axis in liver type 2 mHDC functions, pointing out the importance of CXCR1 in promoting IL-10-mediated anti-inflammatory actions of HDCs.