TRAF6 Contributes to CFA-Induced Spinal Microglial Activation and Chronic Inflammatory Pain in Mice

Lu, Ying; Cao, De‐Li; Ma, Lingjie; Gao, Yong‐Jing

doi:10.1007/s10571-021-01045-y

Cited by 15 publications

(17 citation statements)

References 66 publications

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“…As shown by Lu et al [28], intrathecal injection of DHAin miceexerts an anti-nociceptive effect on in ammatory pain induced by intraplantar injection of carrageenan byinhibiting the activity of p38 mitogen-activated protein kinase in the spinal cord.Moreover, both the NLRX1 ligand DHA itself and specialized pro-resolving mediators synthesized from DHA, such as maresins, resolvins, and protectins,and have been shown to exert analgesic and anti-in ammatory effects in various acute and chronic in ammatory pain models [10,29]. On the other hand, there is only one study showing that intrathecal injection of DHA reduces chronic in ammatory pain as determined by the mechanical allodynia test induced by intrathecal injection of LPS or intraplantar injection of CFAinto mice by inhibiting the up-regulationof TRAF6 in the spinal cord and allograft in ammatory factor 1 (a microglial marker) [13].In the present study, treatment with DHA showed a signinicant improvement in latency compared with endotoxemic mice. DHAalso prevented theLPS-induced increase in K63 Uprotein expression, as well as phosphorylation ofIKKa, IKKβ, and IKKgproteins,in NLRX1-immunoprecipitated tissues.…”

Section: Discussionmentioning

confidence: 99%

“…DHAalso prevented theLPS-induced increase in K63 Uprotein expression, as well as phosphorylation ofIKKa, IKKβ, and IKKgproteins,in NLRX1-immunoprecipitated tissues. On the other hand, treatment with DHA failed to prevent the LPS-induced changes in NLRX1 and TRAF6 protein expression.In the IKKg-immunoprecipitated tissues of LPS-injected mice treated with DHA, IKKa and IKKβ phosphorylation,as well as K63 U and K48 U protein expression,weredecreased.In addition, the LPS-induced decrease in protein expression of IkB-α associated with the increased expression of p-IkB-α,NF-kB p65, p-NF-kB p65,and IL-1βproteins in the tissues was also prevented by treating the mice with DHA.Based on the results of studies in the literature [4,7,10,12,13,21,23,[26][27][28] and our previous ndings on the model of in ammatory hyperalgesia induced by LPS injection [15][16][17][18][19],it appears that reduced formation of pro-in ammatory mediators as a result of inhibition of the TRAF6/IKK/IkB-a/NF-kB signaling pathway at the transcriptional and/or post-transcriptional level in the CNS of mice is involved in the analgesicand anti-in ammatory effects of DHA.It is also possible that increased polyubiquitination via the K63 U, but not the K48 U, linkage after dissociation of NLRX1 from TRAF6 and/or decreased K63 U-and K48 U-linked polyubiquitination of IKKg leading to suppression of IKK/IkB-a/NF-kB signaling pathway activity contribute to the protective effects of DHA against in ammatory hyperalgesia in response to LPS.…”

Section: Discussionmentioning

confidence: 99%

“…This interaction leads to inhibition of phosphorylation of the IKKa/IKKβ catalytic subunits of the IKK complex and NF-κB activation, which isassociated withproin ammatory cytokine formation and mortality.Overall, the results suggest that NLRX1 also serves to prevent excessive host responses to a variety of in ammatory stimuliin vitro and in vivo. In addition, the results of several studiessuggest that w-3 polyunsaturated fatty acids thathave the ability toenter the central nervous system (CNS) [9], such as docosahexaenoic acid (DHA), NLRX1 ligand, have anti-in ammatory effectsby inhibiting NF-κB activity in various neuroin ammation models with NLRX1-dependent mechanism [10][11][12].There is only one study in the literature showing that intrathecal injection of DHA prevents chronic in ammatory pain in mice as tested by punctate mechanical allodynia perceived at the supraspinal level after intrathecal LPS or intraplantar complete Freund's adjuvant (CFA) injection [13].However, there are no studies focusing on either the role of NLRX1 or the effect of NLRX1 ligands in perceived LPS-nduced in ammatory hyperalgesia at the spinal and/or supraspinal level.…”

Section: Introductionmentioning

confidence: 99%

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NLRX1 Ligand, Docosahexaenoic Acid, Ameliorates LPS-Induced Inflammatory Hyperalgesia by Decreasing TRAF6/IKK/IkB-a/NF-kB Signaling Pathway Activity

Yilmaz

Senol

Temiz-Resitoglu

et al. 2022

Preprint

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Objective The nucleotide-binding oligomerization domain-like receptor X1 (NLRX1) has been associated with various anti-inflammatory mechanisms. We investigated whether the NLRX1 ligand docosahexaenoic acid (DHA) ameliorates lipopolysaccharide (LPS)-induced inflammatory hyperalgesia by interacting with tumor necrosis factor receptor-associated factor 6 (TRAF6)/inhibitor of kB (IkB) kinase (IKK)/IkB-a/nuclear factor-κB (NF-κB) signaling pathway in the central nervous system. Methods Reaction time to thermal stimuli within 30 seconds was measured in male mice injected with saline, lipopolysaccharide (LPS), and/or DHA after 6 hours using the hot plate test. Co-immunoprecipitation and immunoblotting studies were performed to determine activation of the TRAF6/IKK/IkB-a/NF-kB pathway in the brains and spinal cords of LPS-treated animals. Results Latency to the thermal stimulus was reduced by 30% in LPS-injected endotoxemic mice compared with saline-injected mice. Treatment with DHA significantly improved latency compared with endotoxemic mice. In the brain and spinal cord of LPS-injected mice, treatment with DHA also prevented the increase in the expression and/or activity of (1) IKK/IKKβ, IKK, and K63 U in the NLRX1-immunoprecipitated tissues, (2) IKK/IKKβ, K63 U, and K48 U in the IKK-immunoprecipitated tissues, and (3) IkB-α, NF-kB p65, and interleukin-1β associated with decreased IkB-α expression. Conclusion Inhibition of IKK/IkB-a/NF-kB signaling by dissociation of NLRX1 from TRAF6 in response to LPS treatment may contribute to the protective effect of DHA against inflammatory hyperalgesia.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

NLRX1 Ligand, Docosahexaenoic Acid, Ameliorates LPS-Induced Inflammatory Hyperalgesia by Decreasing TRAF6/IKK/IkB-a/NF-kB Signaling Pathway Activity

Yilmaz

Senol

Temiz-Resitoglu

et al. 2022

Preprint

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“…Currently available drugs for the treatment of inflammatory pain have various side effects, such as non-steroidal anti-inflammatory drugs (NSAIDs) and opioids. NSAIDs may cause gastrointestinal bleeding, chronic nephritis, and an increased risk of cardiovascular diseases ( Lu et al, 2021 ). The analgesic properties of NSAIDs are insufficient in some patients, and their side effects limit their application in long-term therapy ( Grosch et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Caloric Restriction Alleviates CFA-Induced Inflammatory Pain via Elevating β-Hydroxybutyric Acid Expression and Restoring Autophagic Flux in the Spinal Cord

et al. 2022

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Inflammatory pain is the most common type of pain encountered in clinical practice; however, the currently available treatments are limited by insufficient efficacy and side effects. Therefore, new methods to relieve inflammatory pain targeting new mechanisms are urgently needed. Preclinical investigations have shown that CR (calorie restriction) exerts analgesic effects in neuropathic and cancer pain; however, the effect of CR on chronic inflammatory pain remains unknown. During calorie restriction, autophagy, a lysosome-dependent degradation process, can be activated to support cell survival. In the present study, we investigated the analgesic effects of CR on complete Freund’s adjuvant (CFA)-induced inflammatory pain. The accumulation of LC3-II and p62 showed impaired autophagic flux in the ipsilateral spinal cord of mice with CFA-induced inflammatory pain. CR alleviated mechanical allodynia and thermal hyperalgesia and reduced paw edema and pro-inflammatory factors following CFA administration. CR exerted an analgesic effect by restoring autophagic flux in the spinal cord. Regarding the mechanisms underlying the analgesic effects of CR, β-hydroxybutyric acid (BHB) was studied. CR increased BHB levels in the ipsilateral spinal cord. Furthermore, exogenous BHB administration exerted an analgesic effect by restoring autophagic flux in the spinal cords of CFA-induced inflammatory pain mice. Taken together, these results illustrated that CR relieved inflammatory pain by restoring autophagic flux in the spinal cord, while BHB controlled the benefits of CR, suggesting that CR or BHB might be a promising treatment for inflammatory pain.

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“…CFA-induced inflammation promotes the release of inflammatory mediators from cells, including cytokines (such as TNF-α, IL-1β, and IL-6) and chemokines (such as CCL2, CXCL1, and CX3CL1) [ 19 , 20 ]. Inducible nitric oxide synthase (iNOS) and prostaglandin E2 (PGE2) could increase neuronal excitability and synaptic transmission, leading to pain [ 21 , 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

A Metabolomic Study of the Analgesic Effect of Lappaconitine Hydrobromide (LAH) on Inflammatory Pain

Wang

et al. 2022

Metabolites

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Lappaconitine (LA) is a C-18 diterpene alkaloid isolated from Aconitum sinomontanum Nakai that has been shown to relieve mild to moderate discomfort. Various researchers have tried to explain the underlying mechanism of LA’s effects on chronic pain. This article uses metabolomics technology to investigate the metabolite alterations in the dorsal root ganglion (DRG) when lappaconitine hydrobromide (LAH) was injected in an inflammatory pain model, to explain the molecular mechanism of its analgesia from a metabolomics perspective. The pain model used in this study was a complete Freund’s adjuvant (CFA)-induced inflammatory pain model in rats. There were two treatment groups receiving different dosages of LAH (4 mg/kg LAH and 8 mg/kg LAH). The analgesic mechanism of LAH was investigated with an analgesic behavioral test, tissue sections, and metabolomics. The results of the analgesic behavioral experiment showed that both 4 mg/kg LAH and 8 mg/kg LAH could significantly improve the paw withdrawal latency (PWL) of rats. The tissue section results showed that LAH could reduce the inflammatory response and enlargement of the paw and ankle of rats and that there was no significant difference in the tissue sections of the DRG. The metabolomics results showed that retinol metabolism and glycerophospholipid metabolism in the CFA-induced inflammatory pain model were significantly affected and may exacerbate the inflammatory reactions and initiate persistent pain; in addition, the linoleic acid metabolism, arachidonic acid metabolism, and alanine, aspartate, and glutamate metabolism were also slightly affected. Among them, the alpha-linolenic acid metabolism was up-regulated after LAH treatment, while the retinol metabolism was down-regulated. These results suggest that LAH could effectively reduce inflammatory pain and might achieve this by regulating the lipid metabolism in the rat DRG.

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TRAF6 Contributes to CFA-Induced Spinal Microglial Activation and Chronic Inflammatory Pain in Mice

Cited by 15 publications

References 66 publications

NLRX1 Ligand, Docosahexaenoic Acid, Ameliorates LPS-Induced Inflammatory Hyperalgesia by Decreasing TRAF6/IKK/IkB-a/NF-kB Signaling Pathway Activity

NLRX1 Ligand, Docosahexaenoic Acid, Ameliorates LPS-Induced Inflammatory Hyperalgesia by Decreasing TRAF6/IKK/IkB-a/NF-kB Signaling Pathway Activity

Caloric Restriction Alleviates CFA-Induced Inflammatory Pain via Elevating β-Hydroxybutyric Acid Expression and Restoring Autophagic Flux in the Spinal Cord

A Metabolomic Study of the Analgesic Effect of Lappaconitine Hydrobromide (LAH) on Inflammatory Pain

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