Resolvin D1/N-formyl peptide receptor 2 ameliorates paclitaxel-induced neuropathic pain through the activation of IL-10/Nrf2/HO-1 pathway in mice

Abstract

IntroductionPaclitaxel is a chemotherapy drug that is commonly used to treat cancer, but it can cause paclitaxel-induced neuropathic pain (PINP) as a side effect. Resolvin D1 (RvD1) has been shown to be effective in promoting the resolution of inflammation and chronic pain. In this study, we evaluated the effects of RvD1 on PINP and its underlying mechanisms in mice.MethodsBehavioral analysis was used to assess the establishment of the PINP mouse model and to test the effects of RvD1 or other formulations on mouse pain behavior. Quantitative real-time polymerase chain reaction analysis was employed to detect the impact of RvD1 on 12/15 Lox, FPR2, and neuroinflammation in PTX-induced DRG neurons. Western blot analysis was used to examine the effects of RvD1 on FPR2, Nrf2, and HO-1 expression in DRG induced by PTX. TUNEL staining was used to detect the apoptosis of DRG neurons induced by BMDM conditioned medium. H2DCF-DA staining was used to detect the reactive oxygen species level of DRG neurons in the presence of PTX or RvD1+PTX treated BMDMs CM.ResultsExpression of 12/15-Lox was decreased in the sciatic nerve and DRG of mice with PINP, suggesting a potential involvement of RvD1 in the resolution of PINP. Intraperitoneal injection of RvD1 promoted pain resolution of PINP in mice. Intrathecal injection of PTX-treated BMDMs induced mechanical pain hypersensitivity in naïve mice, while pretreatment of RvD1 in BMDMs prevented it. Macrophage infiltration increased in the DRGs of PINP mice, but it was not affected by RvD1 treatment. RvD1 increased IL-10 expression in the DRGs and macrophages, while IL-10 neutralizing antibody abolished the analgesic effect of RvD1 on PINP. The effects of RvD1 in promoting IL-10 production were also inhibited by N-formyl peptide receptor 2 (FPR2) antagonist. The primary cultured DRG neurons apoptosis increased after stimulation with condition medium of PTX-treated BMDMs, but decreased after pretreatment with RvD1 in BMDMs. Finally, Nrf2-HO1 signaling was additionally activated in DRG neurons after stimulation with condition medium of RvD1+PTX-treated BMDMs, but these effects were abolished by FPR2 blocker or IL-10 neutralizing antibody.DiscussionIn conclusion, this study provides evidence that RvD1 may be a potential therapeutic strategy for the clinical treatment of PINP. RvD1/FPR2 upregulates IL-10 in macrophages under PINP condition, and then IL-10 activates the Nrf2- HO1 pathway in DRG neurons, relieve neuronal damage and PINP.

Role of Resolvins in Inflammatory and Neuropathic Pain

“…Moreover, RvD1 reduced M1 macrophage activity and increased IL-10 expression and anti-inflammatory cytokines in the DRG and sciatic nerve [105]. Sexual dimorphism of RvD5 was reported in the mechanical allodynia regulation of TRPV1 or TRPA1 knock-out CIPN mice [105].…”

“…Therefore, several studies have demonstrated the analgesic effects of Rv series using the CIPN mouse model. Intraperitoneal injection of RvD1 on day 1 after paclitaxel injection attenuated mechanical allodynia and thermal hyperalgesia in response to heat and cold stimuli [105]. Moreover, RvD1 reduced M1 macrophage activity and increased IL-10 expression and anti-inflammatory cytokines in the DRG and sciatic nerve [105].…”

“…Intraperitoneal injection of RvD1 on day 1 after paclitaxel injection attenuated mechanical allodynia and thermal hyperalgesia in response to heat and cold stimuli [105]. Moreover, RvD1 reduced M1 macrophage activity and increased IL-10 expression and anti-inflammatory cytokines in the DRG and sciatic nerve [105]. Sexual dimorphism of RvD5 was reported in the mechanical allodynia regulation of TRPV1 or TRPA1 knock-out CIPN mice [105].…”

“…This surgical neuropathic pain model was developed to mimic peripheral nerve injury and exhibit mechanical allodynia and thermal hyperalgesia [113]. Post-surgical administration of RvD2 at low doses (500 ng) via the intrathecal route and higher doses (5 µg) via the intravenous route significantly attenuated mechanical allodynia and thermal hypersensitivity [105]. In addition, Rv-D2 reduced IL-17 and CXCL1 expression and astrocyte activity in the spinal cord dorsal horn [105].…”

Regulation of the Nrf2/HO-1 axis by mesenchymal stem cells-derived extracellular vesicles: implications for disease treatment

“…Nrf2 is also under the control of many other regulators, such as Akt ( Chen et al, 2022 ), Sirtuins ( Pan et al, 2016 ), IL-10 ( Su et al, 2023 ), and MAPK signaling ( Sun et al, 2009 ), all safeguarding cells from oxidative stress. Under normal conditions, Nrf2 is tightly regulated by the Keap1-CUL3-RBX1 E3 ubiquitin ligase complex, leading to Nrf2 degradation via the ubiquitin-proteasome pathway.…”