A Liver-to-Skin Neuroimmune Axis Transmits Visceral Distress via Midkine-Driven Alloknesis

The skin, long considered as a passive barrier and target of external insults, could also function as a sentinel for internal pathology, although the underlying mechanisms remain poorly understood. Here, we identify a neuroimmune circuit linking liver injury to mechanically evoked itch (alloknesis) in the skin. The hepatokine Midkine (MDK) emerges as a critical circulating signal, elevated in liver injury, which activates skin-resident macrophages through LRP1, inducing NGF production and subsequent sensitization of cutaneous pruriceptors. Importantly, elevated serum Midkine levels in liver disease patients strongly correlated with alloknesis severity, highlighting the conserved liver-skin axis. These findings reveal an inter-organ communication pathway that transduces visceral stress into periphery sensory hyperactivity, establishing the skin as a reflective interface of internal organ dysfunction. Dorsal skin CX3CR1+ cells were collected for smart-seq assay using CCl4 or Vehicle-treated Cx3cr1-creER:Ai9 mice in three biological replicates. Hepatocytes were collected for bulk-RNA seq assay using CCl4 or Vehicle-treated C57 mice in three biological replicates.