Electroacupuncture ameliorates incisional pain via suppressing IL-33 signaling-related macrophage infiltration and ROS overproduction in incised skin

Background: Postoperative pain develops after surgical operation. Inadequately managed postoperative pain is oftentimes associated with deterioration in life quality and delayed rehabilitation. Clinical studies confirmed analgesic effects of acupuncture on patients with postoperative pain. We hereby explored mechanisms underlying how acupuncture alleviates postoperative pain. Methods: A mouse model of skin incision-induced pain was established to mimic postoperative pain condition. Electroacupuncture (EA) or sham EA was administered at ST36 and BL60 acupoints in model mice. A combination of RNA-Sequencing (RNA-Seq), immunostaining, biochemical assay, in vivo imaging and behavioral test were applied for mechanism investigations. Results: 2/100 Hz EA intervention ameliorated mechanical allodynia and improved cumulative pain of incisional pain model mice. Sham EA exerted no obvious analgesic effect. Incisional pain model mice develop gait impairment, which was improved by EA intervention. RNA-Seq identified EA significantly reduced Il33 gene overexpression in the incised skin tissues of model mice. IL-33 was produced from keratinocytes upon skin incision. EA reduced IL-33 overproduction from keratinocytes, resulting in less macrophage infiltration and less ROS accumulation in the incised skin. Adoptive transfer of macrophages into the incised tissue abrogated the ameliorative effects of EA on macrophage infiltration as well as ROS accumulation in incised skin and further reversed EA-induced analgesia on incisional pain model mice. Additionally, EA intervention did not affect skin wound healing process. Conclusion: These results demonstrate that EA ameliorates incisional pain via suppressing IL-33 overproduction in incised skin tissue. EA-induced suppression of IL-33 overproduction results in less macrophage infiltration and ROS accumulation that contribute to analgesia. Our work helps to support EA as an alternative and green therapy for postoperative pain management.