Skin-resident dendritic cells mediate postoperative pain via CCR4 on sensory neurons

Abstract

Significance Interactions between the nervous and immune systems control the generation and maintenance of inflammatory pain. However, the immune cells and mediators controlling this response remain poorly characterized. We identified the cytokines CCL22 and CCL17 as secreted mediators that act directly on sensory neurons to mediate postoperative pain via their shared receptor, CCR4. We also show that skin-resident dendritic cells are key contributors to the inflammatory pain response. Blocking the interaction between these dendritic cell–derived ligands and their receptor can abrogate the pain response, highlighting CCR4 antagonists as potentially effective therapies for postoperative pain. Our findings identify functions for these tissue-resident myeloid cells and uncover mechanisms underlying pain pathophysiology.