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

Abstract

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.

Skin-resident immune cells engulf axonal debris in adult epidermis

“…The relationship between Langerhans cells and these neuropathies is currently poorly understood, but is of potential clinical significance. Recent work suggests that Langerhans cells mediate pain by directly signaling to sensory neurons (Raymondi Silva et al, 2022). Our findings could have relevance for identifying mechanisms that mediate the initiation or progression of peripheral neuropathies and future studies in zebrafish could provide a unique perspective on the role of Langerhans cells in these human diseases.…”

CCL17/TARC in autoimmunity and inflammation—not just a T‐cell chemokine

“…25,28 Systemically administered CCL17 has also been shown to directly induce arthritic pain and disease in methylated bovine serum albumin (BSA)-injected joints, as well as inflammatory pain in mouse paws, with the CCL17-driven inflammatory pain dependent on cyclooxygenase activity, neurotrophins and neuropeptides. 27 These studies indicate a role for CCL17 in the development and progression of inflammatory arthritic pain; however, whether CCL17 acts on neurons directly via CCR4 remains controversial, as one study claimed that peripheral sensory neurons express CCR4, 37 while another study using single-cell RNA-seq detected no CCR4 expression by these cells. 38 As mentioned earlier, patients with RA who receive neutralizing mAbs against GM-CSF or its receptor have reduced circulating CCL17 levels 31 ; these findings are consistent with a functional GM-CSF/CCL17 pathway and serve as supporting evidence for CCL17 to be considered as a biomarker for anti-GM-CSF or anti-GM-CSF receptor treatment in RA and possibly other inflammatory arthritides.…”

“…Systemically administered CCL17 has also been shown to directly induce arthritic pain and disease in methylated bovine serum albumin (BSA)‐injected joints, as well as inflammatory pain in mouse paws, with the CCL17‐driven inflammatory pain dependent on cyclooxygenase activity, neurotrophins and neuropeptides 27 . These studies indicate a role for CCL17 in the development and progression of inflammatory arthritic pain; however, whether CCL17 acts on neurons directly via CCR4 remains controversial, as one study claimed that peripheral sensory neurons express CCR4, 37 while another study using single‐cell RNA‐seq detected no CCR4 expression by these cells 38 …”

Nerve–myeloid cell interactions in persistent human pain: a reappraisal using updated cell subset classifications

“…In murine models, myeloid cells are involved in the initiation and maintenance of chronic pain through interaction with nerve fibres. 52,63,64,83,95,118,122,166,168 For example, macrophages are drawn towards damaged nerves through chemotactic gradients where they phagocytose degenerated nerve fibres and contribute to nerve regeneration 96,107,138 and release proinflammatory cytokines involved in the maintenance of pain. 1,129 Moreover, the depletion of macrophages from the dorsal root ganglion is sufficient to reduce hypersensitivity resulting from nerve injury.…”

“…For example, in the skin, tissue-resident cells that release these cytokines include keratinocytes, 74,97,100,147 fibroblasts, 74 T cells, and immune cells of the myeloid lineage such as macrophages and dendritic cells (DCs). 19,60,122,163 In addition, other cell types infiltrate tissues in response to inflammation and also secrete cytokines, most notably monocytes, plasmacytoid DCs, and helper T cells. 7,48,99,156 Myeloid cells are of particular interest in pain research because they are first responders and mediate early phase inflammatory processes in response to tissue injury through cytokine and chemokine secretions.…”