Maresin 1 Attenuates Radicular Pain Through the Inhibition of NLRP3 Inflammasome-Induced Pyroptosis via NF-κB Signaling

Abstract

Background: The exposure of the nucleus pulposus (NP) causes an immune and inflammatory response, which is intrinsically linked to the pathogenesis of radicular pain. As a newly discovered pro-resolving lipid mediator, maresin 1 (MaR1) could exert powerful inflammatory resolution, neuroprotection, and analgesic activities. In the present research, the analgesic effect of MaR1 was observed. Then, the potential mechanism by which MaR1 attenuated radicular pain was also analyzed in a rat model. Methods: Intrathecal administration of MaR1 (10 or 100 ng) was successively performed in a rat with non-compressive lumbar disk herniation for three postoperative days. Mechanical and thermal thresholds were determined to assess pain-related behavior from days 1 to 7 (n = 8/group). On day 7, the tissues of spinal dorsal horns from different groups were gathered to evaluate expression levels of inflammatory cytokines (IL-1β, IL-18, and TNF-α), the NLRP3 inflammasome and pyroptosis indicators (GSDMD, ASC, NLRP3, and Caspase-1), together with NF-κB/p65 activation (n = 6/group). TUNEL and PI staining were performed to further examine the process of pyroptosis. Results: After intrathecal administration in the rat model, MaR1 exhibited potent analgesic effect dose-dependently. MaR1 significantly prompted the resolution of the increased inflammatory cytokine levels, reversed the up-regulated expression of the inflammasome and pyroptosis indicators, and reduced the cell death and the positive activation of NF-κB/p65 resulting from the NP application on the L5 dorsal root ganglion. Conclusion: This study indicated that the activation of NLRP3 inflammasome and pyroptosis played a significant role in the inflammatory reaction of radicular pain. Also, MaR1 could effectively down-regulate the inflammatory response and attenuate pain by inhibiting NLRP3 inflammasome-induced pyroptosis via NF-κB signaling.

NLRP3 Inflammasome-Mediated Pyroptosis Pathway Contributes to the Pathogenesis of Candida albicans Keratitis

“…To further confirm the presence of pyroptosis in C. albicans -infected mouse corneas, we performed double-immunofluorescence staining. Active CASP1 and TUNEL double positive cells were designated as pyroptotic cells ( 25 ). As shown in Figure 2D , pyroptotic cell death was obviously observed in C. albicans -infected corneas, in contrast, no pyroptotic cell was observed in control group.…”

“…In addition, increasing evidences have shown that the DNA fragmentation during pyroptosis can be labeled by TUNEL-staining ( 28 , 29 ). Therefore, the active CASP1 and TUNEL double-immunofluorescence staining was widely used to detect pyroptosis ( 24 , 25 , 30 ). We found that pyroptotic cells was obviously observed in C. albicans -infected mouse corneas according to CASP1 and TUNEL double-immunofluorescence staining.…”

Maresin-1 and Inflammatory Disease

“…Maresin-1 has also been shown to be effective in chronic pain, when administered between the L4 and L6 vertebrae of the spinal cord and the analgesic effect was observed for 5 days [40]. Regarding the mechanisms, maresin-1 decreased proinflammatory cytokines (IL-1β, IL-18, and TNFα) and reduced NLRP3 inflammasome, leading to the impairment of cell death and positive activation of NF-κB/p65-mediated inflammation and pain [41]; the mechanical and thermal hypersensitivity enhanced the IL-1β and IL-18 levels and the expression of NLRP3 inflammasome components, which were markedly suppressed by maresin-1 treatment [42].…”

Role of Specialized Pro-Resolving Mediators in Neuropathic Pain

“…Intrathecal administration of MaR 1 inhibits the activation of DRG neurons and abates activation of spinal NF-kB and production of TNF-α and IL-1β, resulting in reduced mechanical and thermal hyperalgesia in CFA- and carrageenan-induced pain paradigms, up to 3–5 days after the treatment ( Fattori et al, 2019 ) and in spinal nerve ligation models ( Gao et al, 2018 ). MaR 1 also reduces mechanical allodynia in rat models of radicular pain ( Wang et al, 2020 ), as well as chemotaxis of inflammatory cells in the calcitonin gene-related peptide (CGRP)-releasing DRG neurons ( Fattori et al, 2019 ). In line with this, a recent investigation has shown that intraperitoneal administration of MaR 1 in a K/BxN transfert-based model of arthritic pain led to reduced mechanical hypersensitivity, due to inhibition of macrophage inflammatory chemotaxis in the DRG ( Allen et al, 2020 ).…”