JNK/c-Jun-driven NLRP3 inflammasome activation in microglia contributed to retinal ganglion cells degeneration induced by indirect traumatic optic neuropathy

Chu, Xiaoqi; Wang, Chun; Wu, Zheng; Long, Fan; Chen, Tao; Lin, Jiaqi; Chen, Shuang; Lin, Yongzhong; Ge, Yakun

doi:10.1016/j.exer.2020.108335

Cited by 17 publications

(10 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It was already shown by an in vitro study that minocycline, a glial inhibitor, treatment before LPS stimulation prevented XCL1 mRNA upregulation in primary astroglial cells (7). Our present results confirmed that consecutive minocycline treatment (twice daily, 7 days) attenuates CCI-evoked neuropathic pain by inhibiting microglia/macrophages and diminishing the levels of p38, ERK, JNK and AKT, which is congruent with literature data (13, [45][46][47][48]. It was also demonstrated that minocycline diminished hypersensitivity of spinal neurons after traumatic spinal cord injury (49).…”

Section: Discussionsupporting

confidence: 93%

New insights into the analgesic properties of the XCL1/XCR1 and XCL1/ITGA9 axes modulation under neuropathic pain conditions - evidence from animal studies

et al. 2022

View full text Add to dashboard Cite

Recent studies have indicated the involvement of chemokine-C-motif ligand 1 (XCL1) in nociceptive transmission; however, the participation of its two receptors, canonical chemokine-C-motif receptor 1 (XCR1) and integrin alpha-9 (ITGA9), recently recognized as a second receptor, has not been clarified to date. The aim was to explore by which of these receptors XCL1 reveals its pronociceptive properties and how the XCL1-XCR1 and XCL1-ITGA9 axes blockade/neutralization influence on pain-related behavior and opioid analgesia in the model of neuropathic pain. In our studies we used Albino Swiss mice which were exposed to the unilateral sciatic nerve chronic constriction injury (CCI) as a neuropathic pain model. Animals received single intrathecal (i.t.) injection of XCL1, XCL1 neutralizing antibodies, antagonist of XCR1 (vMIP-II) and neutralizing antibodies of ITGA9 (YA4), using lumbar puncture technique. Additionally we performed i.t. co-administration of abovementioned neutralizing antibodies and antagonists with single dose of morphine/buprenorphine. To assess pain-related behavior the von Frey and cold plate tests were used. To measure mRNA and protein level the RT-qPCR and Western Blot/Elisa/immunofluorescence techniques were performed, respectively. Statistical analysis was conducted using ANOVA with a Bonferroni correction. Presented studies have shown time-dependent upregulation of the mRNA and/or protein expression of XCL1 in the spinal cord after nerve injury as measured on day 1, 4, 7, 14, and 35. Our immunofluorescence study showed that XCL1 is released by astroglial cells located in the spinal cord, despite the neural localization of its receptors. Our results also provided the first evidence that the blockade/neutralization of both receptors, XCR1 and ITGA9, reversed hypersensitivity after intrathecal XCL1 administration in naive mice; however, neutralization of ITGA9 was more effective. In addition, the results proved that the XCL1 neutralizing antibody and, similarly, the blockade of XCR1 and neutralization of ITGA9 diminished thermal and mechanical hypersensitivity in nerve injury-exposed mice after 7 days. Additionally, neutralization of XCL1 improves morphine analgesia. Moreover, blockade of XCR1 positively influences buprenorphine effectiveness, and neutralization of ITGA9 enhances not only buprenorphine but also morphine analgesia. Therefore, blockade of the XCL1-ITGA9 interaction may serve as an innovative strategy for the polypharmacotherapy of neuropathic pain in combination with opioids.

show abstract

Section: Discussionsupporting

confidence: 93%

New insights into the analgesic properties of the XCL1/XCR1 and XCL1/ITGA9 axes modulation under neuropathic pain conditions - evidence from animal studies

et al. 2022

View full text Add to dashboard Cite

show abstract

“…We found that Tlr2 and Tlr4 gene expression was increased on Day 14 (Figure 2D,E), which could be associated with inflammation and the induction of various downstream proteins and activation of the inflammasome. 16 In line with CD68 + myeloid population infiltration in the liver observed in the human CC sample, rodent samples and pub-lished data, 12 we found gene expression for myeloid recruitment protein to be increased, Ccl2; in addition, markers of CD68 + myeloid population, F4/80 and Cd68, also increased during cancer-cachexia development (Figure S2A-C). L-1β gene expression was higher on Day 7 and still increasing on Day 14 (Figure 2F) and then accompanied by higher Il-1β protein levels in the organ (Figure 3A).…”

Section: Resultssupporting

confidence: 80%

“…None of these were statistically different for any of the time points analysed ( Figure –), suggesting that the NF‐κB pathway does not play a role in rodent hepatic inflammation. We found that Tlr2 and Tlr4 gene expression was increased on Day 14 ( Figure ,), which could be associated with inflammation and the induction of various downstream proteins and activation of the inflammasome 16 . In line with CD68 + myeloid population infiltration in the liver observed in the human CC sample, rodent samples and published data, 12 we found gene expression for myeloid recruitment protein to be increased, Ccl2 ; in addition, markers of CD68 + myeloid population, F4/80 and Cd68 , also increased during cancer‐cachexia development ( Figure A – C ).…”

Section: Resultsmentioning

confidence: 83%

Cachexia causes time‐dependent activation of the inflammasome in the liver

Neves

Yamashita

Riccardi

et al. 2023

J cachexia sarcopenia muscle

View full text Add to dashboard Cite

Background Cachexia is a wasting syndrome associated with systemic inflammation and metabolic disruption. Detection of the early signs of the disease may contribute to the effective attenuation of associated symptoms. Despite playing a central role in the control of metabolism and inflammation, the liver has received little attention in cachexia. We previously described relevant disruption of metabolic pathways in the organ in an animal model of cachexia, and herein, we adopt the same model to investigate temporal onset of inflammation in the liver. The aim was thus to study inflammation in rodent liver in the well‐characterized cachexia model of Walker 256 carcinosarcoma and, in addition, to describe inflammatory alterations in the liver of one cachectic colon cancer patient, as compared to one control and one weight‐stable cancer patient. Methods Colon cancer patients (one weight stable [WSC] and one cachectic [CC]) and one patient undergoing surgery for cholelithiasis (control, n = 1) were enrolled in the study, after obtainment of fully informed consent. Eight‐week‐old male rats were subcutaneously inoculated with a Walker 256 carcinosarcoma cell suspension (2 × 107 cells in 1.0 mL; tumour‐bearing [T]; or phosphate‐buffered saline—controls [C]). The liver was excised on Days 0 (n = 5), 7 (n = 5) and 14 (n = 5) after tumour cell injection. Results In rodent cachexia, we found progressively higher numbers of CD68+ myeloid cells in the liver along cancer‐cachexia development. Similar findings are described for CC, whose liver showed infiltration of the same cell type, compared with both WSC and control patient organs. In advanced rodent cachexia, hepatic phosphorylated c‐Jun N‐terminal kinase protein content and the inflammasome pathway protein expression were increased in relation to baseline (P < 0.05). These changes were accompanied by augmented expression of the active interleukin‐1β (IL‐1β) form (P < 0.05 for both circulating and hepatic content). Conclusions The results show that cancer cachexia is associated with an increase in the number of myeloid cells in rodent and human liver and with modulation of hepatic inflammasome pathway. The latter contributes to the aggravation of systemic inflammation, through increased release of IL‐1β.

show abstract

“…Past studies have shown that the JNK/c-Jun pathway serves crucial roles in the microglial response and kaempferol attenuates retinal ganglion cell death by suppressing the NLRP3 inflammasome through JNK pathways in acute glaucoma ( 52 , 53 ). A previous study ( 54 ) indicated that indirect traumatic optic neuropathy induces significant retinal ganglion cell (RGC) death and axonal degeneration and activates JNK/c-Jun signaling, which could further induce the microglial response and NLRP3 inflammasome activation. Moreover, JNK disruption suppresses NLRP3 inflammasome activation in microglia and prevents RGC death and axonal degeneration ( 54 ).…”

Section: Discussionmentioning

confidence: 99%

“…A previous study ( 54 ) indicated that indirect traumatic optic neuropathy induces significant retinal ganglion cell (RGC) death and axonal degeneration and activates JNK/c-Jun signaling, which could further induce the microglial response and NLRP3 inflammasome activation. Moreover, JNK disruption suppresses NLRP3 inflammasome activation in microglia and prevents RGC death and axonal degeneration ( 54 ). A previous study found that spleen tyrosine kinase (Syk) and JNK are rapidly phosphorylated during Staphylococcus aureus infection.…”

Section: Discussionmentioning

confidence: 99%

Involvement of the JNK/HO‑1/FTH1 signaling pathway in nanoplastic‑induced inflammation and ferroptosis of BV2 microglia cells

Sun

Wang

et al. 2023

Int J Mol Med

View full text Add to dashboard Cite

Nanoplastics (NPs) are a newly discovered type of environmental pollutant. The potential for neurotoxicity caused by NPs and their mechanisms are unclear. The present study aimed to determine the molecular mechanism underlying neurotoxicity induced by NPs. Microglia (BV2) cells were used for in vitro studies, and it was found that NPs invaded cells, activated inflammasomes, induced the release of significant quantities of inflammatory factors by detection of inflammatory response-associated proteins through Western blot and ELISA. By detection of FITC, SOD, GSH, cellular iron level, and ferroptosis-related proteins, it was found that NPs compromised the anti-oxidative mechanisms of cells, increased intracellular lipid peroxidation and Fe 2+ concentration and triggered inflammatory reactions and ferroptosis. Pretreatment with reactive oxygen species (ROS) inhibitor N-acetylcysteine (NAC) alleviated induction of inflammatory reactions and ferroptosis of cells. In addition, inhibiting expression of c-Jun N-terminal kinase (JNK) increased expression of heme oxygenase (HO-1), resulting in decreased ferroptosis, indicating that the JNK/HO-1 signaling pathway was involved in NP-induced effects on ferroptosis in BV2 cells. In conclusion, NPs could induce inflammatory responses and ferroptosis in BV2 cells. JNK/HO-1 mediated ferroptosis may serve an important role in the toxicity of microglia induced by NPs. This study provided novel evidence for the toxic effects of NPs and highlighted a theoretical mechanistic basis for safe prevention and treatment of plastic pollution-induced neurotoxicity.

show abstract

JNK/c-Jun-driven NLRP3 inflammasome activation in microglia contributed to retinal ganglion cells degeneration induced by indirect traumatic optic neuropathy

Cited by 17 publications

References 37 publications

New insights into the analgesic properties of the XCL1/XCR1 and XCL1/ITGA9 axes modulation under neuropathic pain conditions - evidence from animal studies

New insights into the analgesic properties of the XCL1/XCR1 and XCL1/ITGA9 axes modulation under neuropathic pain conditions - evidence from animal studies

Cachexia causes time‐dependent activation of the inflammasome in the liver

Involvement of the JNK/HO‑1/FTH1 signaling pathway in nanoplastic‑induced inflammation and ferroptosis of BV2 microglia cells

Contact Info

Product

Resources

About