LAUSR

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. Inflammatory pain, such as hypersensitivity resulting from surgical tissue injury, occurs as a result of interactions between the immune and nervous systems with the orchestrated recruitment and activation of tissue-resident and circulating immune cells to the site of injury. Our previous studies identified a central role for Ly6Clow myeloid cells in the pathogenesis of postoperative pain. We now show that the chemokines CCL17 and CCL22, with their cognate receptor CCR4, are key mediators of this response. Both chemokines are up-regulated early after tissue injury by skin-resident dendritic and Langerhans cells to act on peripheral sensory neurons that express CCR4. CCL22, and to a lesser extent CCL17, elicit acute mechanical and thermal hypersensitivity when administered subcutaneously; this response abrogated by pharmacological blockade or genetic silencing of CCR4. Electrophysiological assessment of dissociated sensory neurons from naïve and postoperative mice showed that CCL22 was able to directly activate neurons and enhance their excitability after injury. These responses were blocked using C 021 and small interfering RNA (siRNA)-targeting CCR4. Finally, our data show that acute postoperative pain is significantly reduced in mice lacking CCR4, wild-type animals treated with CCR4 antagonist/siRNA, as well as transgenic mice depleted of dendritic cells. Together, these results suggest an essential role for the peripheral CCL17/22:CCR4 axis in the genesis of inflammatory pain via direct communication between skin-resident dendritic cells and sensory neurons, opening therapeutic avenues for its control.