CXCR3 chemokine receptor signaling mediates itch in experimental allergic contact dermatitis.
Persistent itch is a common symptom of allergic contact dermatitis (ACD) and represents a significant health burden. The chemokine CXCL10 is predominantly produced by epithelial cells during ACD. Although the chemokine CXCL10 and its receptor CXCR3 are implicated in the pathophysiology of ACD, it is largely unexplored for itch and pain accompanying this disorder. Here, we showed that CXCL10 and CXCR3 mRNA, protein, and signaling activity were upregulated in the dorsal root ganglion after contact hypersensitivity (CHS), a murine model of ACD, induced by squaric acid dibutylester. CXCL10 directly activated a subset of cutaneous dorsal root ganglion neurons innervating the area of CHS through neuronal CXCR3. In behavioral tests, a CXCR3 antagonist attenuated spontaneous itch- but not pain-like behaviors directed to the site of CHS. Injection of CXCL10 into the site of CHS elicited site-directed itch- but not pain-like behaviors, but neither type of CXCL10-evoked behaviors was observed in control mice. These results suggest that CXCL10/CXCR3 signaling mediates allergic itch but not inflammatory pain in the context of skin inflammation. Thus, upregulation of CXCL10/CXCR3 signaling in sensory neurons may contribute to itch associated with ACD. Targeting the CXCL10/CXCR3 signaling might be beneficial for the treatment of allergic itch.
Department of Anesthesiology, Yale University School of Medicine, New Haven, CT, USA Department of Neurosurgery, Neurosurgery Pain Research Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
Lintao
L
Qu
Kai
K
Fu
Jennifer
J
Yang
Steven G
SG
Shimada
Robert H
RH
LaMotte
D000081:Acetamides / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D017449:Dermatitis, Allergic Contact / Q000150:complications*; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000166:cytology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects; D011537:Pruritus / Q000188:drug therapy / Q000209:etiology*; D011744:Pyrimidinones / Q000494:pharmacology / Q000627:therapeutic use; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D012867:Skin / Q000294:innervation; D015854:Up-Regulation / Q000187:drug effects
D000081:Acetamides; D018926:Anti-Allergic Agents; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; C515188:Cxcr3 protein, mouse; C546475:MrgprA3 protein, mouse; C497098:Mrgprd protein, mouse; C541505:N-(1-(3-(4-ethoxyphenyl)-4-oxo-3,4-dihydropyrido(2,3-d)pyrimidin-2-yl)ethyl)-N-pyridin-3-ylmethyl-2-(4-trifluoromethoxyphenyl)acetamide; D011744:Pyrimidinones; D054367:Receptors, CXCR3; D043562:Receptors, G-Protein-Coupled