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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 119; no. 4; p. 1
• Main Authors: Silva, Jaqueline Raymondi, Iftinca, Mircea, Fernandes Gomes, Francisco I, Segal, Julia P, Smith, Olivia M A, Bannerman, Courtney A, Silva Mendes, Atlante, Defaye, Manon, Robinson, Madeline E C, Gilron, Ian, Cunha, Thiago Mattar, Altier, Christophe, Ghasemlou, Nader
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 25.01.2022
• Subjects: Action Potentials; Animals; Biological Sciences; Biomarkers; CCL17 protein; CCL22 protein; Cell interactions; Chemokine CCL17 - genetics; Chemokine CCL17 - metabolism; Chemokine CCL22 - genetics; Chemokine CCL22 - metabolism; Chemokines; Dendritic cells; Dendritic structure; Disease Models, Animal; Disease Susceptibility; Excitability; Gene Expression Profiling; Hypersensitivity; Immune system; Inflammation; Injuries; Langerhans cells; Langerhans Cells - immunology; Langerhans Cells - metabolism; Mice; Myeloid cells; Neurons; Pain; Pain, Postoperative - diagnosis; Pain, Postoperative - etiology; Pain, Postoperative - metabolism; Pathogenesis; Receptors, CCR4 - metabolism; Sensory neurons; Sensory Receptor Cells - metabolism; Signal Transduction; siRNA; Skin; Tissues; Transgenic mice; pain; cytokines; myeloid cells; electrophysiology; inflammation
• DOI: 10.1073/pnas.2118238119
• ISSN: 0027-8424

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 Ly6C 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.