Lipoxin A4 Inhibits NLRP3 Inflammasome Activation in Rats With Non-compressive Disc Herniation Through the JNK1/Beclin-1/PI3KC3 Pathway

Jin, Jin; Xie, Yonggang; Shi, Cunxian; Ma, Jiahai; Wang, Yihao; Qiao, Leyan; Li, Kezhong; Sun, Tao

doi:10.3389/fnins.2020.00799

Cited by 14 publications

(16 citation statements)

References 32 publications

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“…LXA4 ameliorates neurological function and reduces cell apoptosis and oxidative stress in a rabbit model of ischemia–reperfusion‐induced SCI [ 17 ]. LXA4 exerts an anti‐inflammatory function in a rat model of noncompressive disk herniation by suppressing activation of NLRP3 inflammasome via the c‐Jun NH2‐terminal kinase 1/beclin‐1/class III phosphatidylinositol‐3‐kinase signaling pathway [ 18 ]. Ferroptosis is an iron‐dependent nonapoptotic cell death that plays a crucial role in SCI [ 2 ].…”

Section: Discussionmentioning

confidence: 99%

Lipoxin A4 protects primary spinal cord neurons from Erastin‐induced ferroptosis by activating the Akt/Nrf2/HO‐1 signaling pathway

Wei

Liu

et al. 2021

FEBS Open Bio

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Ferroptosis is an iron‐dependent programmed cell death, which participates in the pathogenesis of spinal cord injury (SCI). Our previous study has revealed that Lipoxin A4 (LXA4) exerts a protective role in SCI. Here, we investigated whether LXA4 can protect SCI through inhibiting neuronal ferroptosis. We treated primary spinal cord neurons with Erastin (ferroptosis activator) to induce ferroptosis. Erastin treatment reduced cell viability and enhanced cell death of primary spinal cord neurons, which was rescued by ferrostatin‐1 (ferroptosis inhibitor). Moreover, Erastin repressed glutathione peroxidase 4 (GPX4) expression and the levels of glutathione and cysteine in primary spinal cord neurons. Erastin also enhanced the expression of ferroptosis biomarkers (PTGS2 and ACSL4) and the levels of reactive oxygen species (ROS) in primary spinal cord neurons. The influence conferred by Erastin was effectively abolished by LXA4 treatment. Furthermore, LXA4 enhanced the protein expression of p‐AKT, nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) and haem‐oxygenase‐1 (HO‐1) in primary spinal cord neurons. LXA4‐mediated inhibition of ferroptosis of primary spinal cord neurons was prohibited by LY294002 (AKT inhibitor), brusatol (Nrf2 inhibitor) or zinc protoporphyrin (HO‐1 inhibitor). In conclusion, this work demonstrated that LXA4 exerted a neuroprotective effect in Erastin‐induced ferroptosis of primary spinal cord neurons by activating the Akt/Nrf2/HO‐1 signaling pathway. Thus, this work provides novel insights into the mechanisms of action of LXA4 in ferroptosis of primary spinal cord neurons and indicates that LXA4 may be a potential therapeutic agent for SCI.

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Section: Discussionmentioning

confidence: 99%

Lipoxin A4 protects primary spinal cord neurons from Erastin‐induced ferroptosis by activating the Akt/Nrf2/HO‐1 signaling pathway

Wei

Liu

et al. 2021

FEBS Open Bio

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“…LXA4 has been shown to accelerate the resolution phase of in ammation in in vitro studies, animal models, and a variety of in ammation-associated illnesses such as asthma, periodontal disease, atherosclerosis, cystic brosis, gastrointestinal disease, and acute lung injury [22]. LXA4 has also been shown to have anti-in ammatory activity, decreasing the release of pro-in ammatory factors and the in ltrative ability of in ammation cells, and facilitating the chemotaxis and recruitment of macrophages [23,24]. This study focused on the in vitro effects of LXA4 at three concentrations (1, 10, and 100 nM) on M0-, M1-, and M2-polarized macrophages, in order to study its possible effect on the regulation of in ammation and on the phenotypic modulation of macrophages.…”

Section: Discussionmentioning

confidence: 99%

Polarizing properties of lipoxin A4 on THP-1 macrophages in vitro

Aubeux,

Tessier,

Perez

et al. 2022

Preprint

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Lipoxin A4 (LXA4) is a specialized pro-resolving mediator involved in the resolution phase of inflammation that is crucial for the return of tissues to homeostasis, healing, and regenerative processes. LXA4 acts via its receptor, formyl peptide receptor 2 (FPR2), to promote macrophage polarization. The objective of this study was to assess the effect of LXA4 on macrophage activity and on the phenotype modulation of polarized M1 and M2 macrophages derived from THP-1 monocytes. Once differentiated, human macrophages were incubated with interleukin 4 (IL-4) and IL-13 to obtain M2-polarized macrophages or with interferon gamma and lipopolysaccharide for classical macrophage activation. The mRNA and protein expression of M1 and M2 markers confirmed the polarization of THP-1-derived macrophages. LXA4 (0-100nM) did not affect the viability of M1 and M2 macrophages or the phagocytic activity of these cells. Gene expression of FPR2, referred as a receptor for the LXA4, was higher in M1 compared with M2, and was not modified by the LXA4 at the doses used. Moreover, LXA4 exhibited anti-inflammatory effects by decreasing the gene expression of pro-inflammatory cytokines (IL-6, tumor necrosis factor alpha, IL-1β) in M1 and increasing the expression of anti-inflammatory cytokines (IL-10) in M2. These results provide new insights regarding the potential of LXA4 to switch the polarization state of macrophages.

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“…Autophagy plays an important role in the regulation of the in ammatory response [36,37]. The decrease in autophagy leads to a large number of depolarized mitochondria and leaked substances, including mitochondrial DNA and ROS [38,39]. In addition, there is increasing evidence to suggest that moderating autophagy can promote the polarization of macrophages from the M1 to the M2 phenotype, while the ensuing de ciency of autophagy-related genes could drive the upregulation of M1 polarization [40][41][42].…”

Section: Discussionmentioning

confidence: 99%

Kaempferol alleviates corneal transplantation rejection by inhibiting NLRP3 inflammasome activation and macrophage M1 polarization via promoting autophagy

Tian

Lin

et al. 2021

Experimental Eye Research

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Corneal transplantation rejection remains a major threat to the success rate in high-risk patients. Given the many side effects presented by traditional immunosuppressants, there is an urgency to clarify the mechanism of corneal transplantation rejection and to identify new therapeutic targets. Kaempferol is a natural avonoid that has been proven in various studies to possess anti-in ammatory, antioxidant, anticancer, and neuroprotective properties. However, the relationship between kaempferol and corneal transplantation remains largely unexplored. To address this, both in vivo and in vitro, we established a model of corneal allograft transplantation in Wistar rats and an LPS-induced in ammatory model in THP-1 derived human macrophages. In the transplantation experiments, we observed an enhancement in the NLRP3 / IL-1 β axis and in M1 macrophage polarization post-operation. In groups to which kaempferol intraperitoneal injections were administered, this response was effectively reduced. However, the effect of kaempferol was reversed after the application of autophagy inhibitors. Similarly, in the in ammatory model, we found that different concentrations of kaempferol can reduce the LPS-induced M1 polarization and NLRP3 in ammasome activation. Moreover, we con rmed that kaempferol induced autophagy and that autophagy inhibitors reversed the effect in macrophages. In conclusion, we found that kaempferol can inhibit the activation of the NLRP3 in ammasomes by inducing autophagy, thus inhibiting macrophage polarization, and ultimately alleviating corneal transplantation rejection. Thus, our study suggests that kaempferol could be used as a potential therapeutic agent in the treatment of allograft rejection.

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Lipoxin A4 Inhibits NLRP3 Inflammasome Activation in Rats With Non-compressive Disc Herniation Through the JNK1/Beclin-1/PI3KC3 Pathway

Cited by 14 publications

References 32 publications

Lipoxin A4 protects primary spinal cord neurons from Erastin‐induced ferroptosis by activating the Akt/Nrf2/HO‐1 signaling pathway

Lipoxin A4 protects primary spinal cord neurons from Erastin‐induced ferroptosis by activating the Akt/Nrf2/HO‐1 signaling pathway

Polarizing properties of lipoxin A4 on THP-1 macrophages in vitro

Kaempferol alleviates corneal transplantation rejection by inhibiting NLRP3 inflammasome activation and macrophage M1 polarization via promoting autophagy

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