Advanced oxidation protein products induce microglia-mediated neuroinflammation via MAPKs-NF-κB signaling pathway and pyroptosis after secondary spinal cord injury
Open accessAbstract
BACKGROUND: Inflammatory response mediated by oxidative stress is considered as an important pathogenesis of spinal cord injury (SCI). Advanced oxidation protein products (AOPPs) are novel markers of oxidative stress and their role in inflammatory response after SCI remained unclear. This study aimed to investigate the role of AOPPs in SCI pathogenesis and explore the possible underlying mechanisms. METHODS: A C5 hemi-contusion injury was induced in Sprague-Dawley rats to confirm the involvement of AOPPs after SCI. For in vivo study, apocynin, the NADPH oxidase inhibitor was used to study the neuroprotective effects after SCI. For in vitro study, the BV2 microglia cell lines were pretreated with or without the inhibitor or transfected with or without small interference RNA (siRNA) and then stimulated with AOPPs. A combination of molecular and histological methods was used to clarify the mechanism and explore the signaling pathway both in vivo and in vitro. One-way analysis of variance (ANOVA) was conducted with Bonferroni post hoc tests to examine the differences between groups. RESULTS: The levels of AOPPs in plasma and cerebrospinal fluid as well as the contents in the spinal cord showed significant increase after SCI. Meanwhile, apocynin ameliorated tissue damage in the spinal cord after SCI, improving the functional recovery. Immunofluorescence staining and western blot analysis showed activation of microglia after SCI, which was in turn inhibited by apocynin. Pretreated BV2 cells with AOPPs triggered excessive generation of reactive oxygen species (ROS) by activating NADPH oxidase. Increased ROS induced p38 MAPK and JNK phosphorylation, subsequently triggering nuclear translocation of NF-κB p65 to express pro-inflammatory cytokines. Also, treatment of BV2 cells with AOPPs induced NLRP3 inflammasome activation and cleavage of Gasdermin-d (GSDMD), causing pyroptosis. This was confirmed by cleavage of caspase-1, production of downstream mature interleukin (IL)-1β and IL-18 as well as rupture of rapid cell membrane. CONCLUSIONS: Collectively, these data indicated AOPPs as biomarkers of oxidative stress, modulating inflammatory response in SCI by multiple signaling pathways, which also included the induction of NADPH oxidase dependent ROS, and NLRP3-mediated pyroptosis, and activation of MAPKs and NF-κB.
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ROS may contribute to microglial activation via p38 and JNK activation.
“ROS may contribute to microglial activation via p38 and JNK activation.”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [155]
Knockdown of NOX4 by RNAi reduced NLRP3 activation.
“Knockdown of NOX4 by RNAi reduced NLRP3 activation, suggesting a potential target to reduce NLRP3-stimulated pathology in neurodegenerative disease [155].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [155]
ROS from NOX4 contribute to activation of the NLRP3 inflammasome.
“ROS from NOX4 also contribute to activation of the NLRP3 inflammasome, a driver of both amyloid-β [156] and tau [23] pathology.”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [155]
ROS originating from NOX4 activation may be important in activating microglia in response to neuronal damage via stimulation of p38 MAPK and JNK.
“Thus, ROS originating from NOX4 activation may be important in activating microglia in response to neuronal damage via stimulation of p38 MAPK and JNK.”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [155]
In a model of spinal cord injury, apocynin reduced activation of p38 MAPK and JNK and expression of TNFα and IL1β.
“In a model of spinal cord injury, apocynin, a NOX-inhibitor (see above), reduced activation of p38 MAPK and JNK and expression of TNFα and IL1β [155].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [155]
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Cites
Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death
Shi, J., Zhao, Y., Wang, K., Shi, X., Wang, Y., Huang, H., Zhuang, Y., Cai, T., Wang, F., & Shao, F. (2015) · Nature · doi:10.1038/nature15514 · Cited by 6,659 · see citing works
Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling
Kayagaki, N., Stowe, I. B., Lee, B. L., O’Rourke, K., Anderson, K., Warming, S., Cuellar, T., Haley, B., Roose-Girma, M., Phung, Q. T., et al. (2015) · Nature · doi:10.1038/nature15541 · Cited by 3,686 · see citing works
Activation and regulation of the inflammasomes
Latz, E., Xiao, T. S., & Stutz, A. (2013) · Nature Reviews Immunology · doi:10.1038/nri3452 · Cited by 2,884 · see citing works
Pore-forming activity and structural autoinhibition of the gasdermin family
Ding, J., Wang, K., Liu, W., She, Y., Sun, Q., Shi, J., Sun, H., Wang, D.-C., & Shao, F. (2016) · Nature · doi:10.1038/nature18590 · Cited by 2,771 · see citing works
Innate Immune Activation Through Nalp3 Inflammasome Sensing of Asbestos and Silica
Dostert, C., Pétrilli, V., Van Bruggen, R., Steele, C., Mossman, B. T., & Tschopp, J. (2008) · Science · doi:10.1126/science.1156995 · Cited by 2,658 · see citing works
Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion
He, W.-T., Wan, H., Hu, L., Chen, P., Wang, X., Huang, Z., Yang, Z.-H., Zhong, C.-Q., & Han, J. (2015) · Cell Research · doi:10.1038/cr.2015.139 · Cited by 2,517 · see citing works
Advanced oxidation protein products as a novel marker of oxidative stress in uremia
Witko‐Sarsat, V., Friedlander, M. A., Capeillère‐Blandin, C., Nguyen‐Khoa, T., Nguyen, A., Zingraff, J., Jungers, P., & Descamps‐Latscha, B. (1996) · Kidney International · doi:10.1038/ki.1996.186 · Cited by 2,000 · see citing works
Repertoire of microglial and macrophage responses after spinal cord injury
David, S., & Kroner, A. (2011) · Nature reviews. Neuroscience · doi:10.1038/nrn3053 · Cited by 1,437 · see citing works
GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death
Sborgi, L., Rühl, S., Mulvihill, E., Pipercevic, J., Heilig, R., Stahlberg, H., Farady, C. J., Müller, D. J., Broz, P., & Hiller, S. (2016) · The EMBO Journal · doi:10.15252/embj.201694696 · Cited by 1,152 · see citing works
Regulation of inflammasome signaling
Rathinam, V. A. K., Vanaja, S. K., & Fitzgerald, K. A. (2012) · Nature Immunology · doi:10.1038/ni.2237 · Cited by 927 · see citing works
GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes
Aglietti, R. A., Estevez, A., Gupta, A., Ramirez, M. G., Liu, P. S., Kayagaki, N., Ciferri, C., Dixit, V. M., & Dueber, E. C. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1607769113 · Cited by 898 · see citing works
Walsh, J. G., Muruve, D. A., & Power, C. (2014) · Nature Reviews Neuroscience · doi:10.1038/nrn3638 · Cited by 637 · cited 2× · see citing works
“NLRP3 inflammasome has been investigated in several CNS diseases, such as traumatic spinal cord injury and Alzheimer’s disease [13, 47].”
Role of microglia in CNS inflammation
Graeber, M. B., Li, W., & Rodriguez, M. L. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.08.033 · Cited by 392 · cited 1× · see citing works
“Microglia are major innate immune cells of the central nervous system (CNS) and play a prominent role in neuroinflammation [4].”
Grace, P. M., Strand, K. A., Galer, E. L., Urban, D. J., Wang, X., Baratta, M. V., Fabisiak, T., Anderson, N. D., Cheng, K., Greene, L. I., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1602070113 · Cited by 363 · see citing works
Inflammation and apoptosis: linked therapeutic targets in spinal cord injury
Beattie, M. S. (2004) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2004.10.006 · Cited by 353 · see citing works
Microglial/Macrophage Polarization Dynamics following Traumatic Brain Injury
Kumar, A., Alvarez-Croda, D.-M., Stoica, B. A., Faden, A. I., & Loane, D. J. (2016) · Journal of Neurotrauma · doi:10.1089/neu.2015.4268 · Cited by 339 · see citing works
Oxidative stress in spinal cord injury and antioxidant-based intervention
Jia, Z., Zhu, H., Li, J., Wang, X., Misra, H., & Li, Y. (2011) · Spinal Cord · doi:10.1038/sc.2011.111 · Cited by 330 · see citing works
Gensel, J. C., Tovar, C. A., Hamers, F. P. T., et al. (2006) · Journal of Neurotrauma · doi:10.1089/neu.2006.23.36 · Cited by 245 · see citing works
Modulatory mechanisms controlling the NLRP3 inflammasome in inflammation: recent developments
Haneklaus, M., O'Neill, L. A. J., & Coll, R. C. (2013) · Current Opinion in Immunology · doi:10.1016/j.coi.2012.12.004 · Cited by 230 · see citing works
Xu, X.-E., Liu, L., Wang, Y.-C., Wang, C.-T., Zheng, Q., Liu, Q.-X., Li, Z.-F., Bai, X.-J., & Liu, X.-H. (2019) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2019.05.038 · Cited by 211 · see citing works
Human nlrp3 inflammasome activation is nox1-4 independent
van Bruggen, R., Köker, M. Y., Jansen, M., van Houdt, M., Roos, D., Kuijpers, T. W., & van den Berg, T. K. (2010) · Blood · doi:10.1182/blood-2009-10-250803 · Cited by 202 · see citing works
Targeting the NLRP3 inflammasome to attenuate spinal cord injury in mice
Jiang, W., Li, M., He, F., Zhou, S., & Zhu, L. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-017-0980-9 · Cited by 185 · see citing works
Self-citationInflammasomes in neurological diseases: emerging pathogenic and therapeutic concepts
Mamik, M. K., & Power, C. (2017) · Brain : a journal of neurology · doi:10.1093/brain/awx133 · Cited by 151 · see citing works
Advanced Oxidation Protein Products Accelerate Renal Fibrosis in a Remnant Kidney Model
Li, H. Y., Hou, F. F., Zhang, X., Chen, P. Y., Liu, S. X., Feng, J., Liu, Z., Shan, Y., Wang, G. B., Zhou, Z. M., et al. (2007) · Journal of the American Society of Nephrology · doi:10.1681/asn.2006070781 · Cited by 132 · see citing works
Self-citationYauger, Y. J., Bermudez, S., Moritz, K. E., Glaser, E. P., Stoica, B. A., & Byrnes, K. R. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1430-7 · Cited by 125 · see citing works
A Key Role for Redox Signaling in Rapid P2X7 Receptor-Induced IL-1β Processing in Human Monocytes
Hewinson, J., Moore, S., Glover, C., Watts, A. G., & Mackenzie, A. B. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.12.8410 · Cited by 122 · see citing works
Lee, S. W., Vaccari, J. P. D. R., Truettner, J. S., Dietrich, W. D., & Keane, R. W. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1423-6 · Cited by 114 · see citing works
Swaroop, S., Mahadevan, A., Shankar, S. K., Adlakha, Y. K., & Basu, A. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1214-5 · Cited by 107 · see citing works
Chen, H.-C., Fong, T.-H., Hsu, P., & Chiu, W. (2012) · Journal of Surgical Research · doi:10.1016/j.jss.2012.02.023 · Cited by 106 · see citing works
Liu, R., Zou, M., Wang, J., Zhu, J., Lai, J.-M., Zhou, L.-L., Chen, S., Zhang, X., & Zhu, J. (2014) · Journal of Neuroinflammation · doi:10.1186/1742-2094-11-47 · Cited by 100 · see citing works
Caspase-11 Controls Interleukin-1β Release through Degradation of TRPC1
Py, B. F., Jin, M., Desai, B. N., Penumaka, A., Zhu, H., Kober, M., Dietrich, A., Lipinski, M. M., Henry, T., Clapham, D. E., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.02.015 · Cited by 93 · see citing works
Liu, G., Fan, G., Guo, G., Kang, W., Wang, D., Xu, B., & Zhao, J. (2016) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-016-0422-8 · Cited by 93 · see citing works
von Leden, R. E., Yauger, Y. J., Khayrullina, G., & Byrnes, K. R. (2016) · Journal of Neurotrauma · doi:10.1089/neu.2016.4486 · Cited by 90 · see citing works
Škvařilová, M., Bulava, A., Stejskal, D., Adamovská, S., & Bartek, J. (2005) · Biomedical Papers · doi:10.5507/bp.2005.009 · Cited by 85 · see citing works
Cell death–mediated cytokine release and its therapeutic implications
Place, D. E., & Kanneganti, T. (2019) · The Journal of Experimental Medicine · doi:10.1084/jem.20181892 · Cited by 84 · see citing works
Xie, F., Sun, S., Xu, A., Zheng, S., Xue, M., Wu, P., Zeng, J. H., & Bai, L. (2014) · Cell Death and Disease · doi:10.1038/cddis.2013.542 · Cited by 78 · see citing works
Gensel, J. C., Donnelly, D. J., & Popovich, P. G. (2011) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2011.553605 · Cited by 77 · see citing works
Zhou, H., Wang, L., Xu, Q., Fan, Z., Zhu, Y., Jiang, H., Zheng, X.-J., Ma, Y.-H., & Zhan, R. (2016) · Experimental Cell Research · doi:10.1016/j.yexcr.2016.09.020 · Cited by 71 · see citing works
Fan, H., Wu, P., Zhang, L., Hu, Z., Wang, W., Guan, X., Luo, H., Ni, M., Yang, J., Li, M., et al. (2015) · Antioxidants and Redox Signaling · doi:10.1089/ars.2014.6022 · Cited by 66 · see citing works
Self-citationSandrow-Feinberg, H. R., Shumsky, J. S., Amin, A., & Houlé, J. D. (2008) · Experimental Neurology · doi:10.1016/j.expneurol.2007.11.029 · Cited by 57 · see citing works
Cooney, S. J., Zhao, Y., & Byrnes, K. R. (2014) · Free Radical Research · doi:10.3109/10715762.2014.927578 · Cited by 55 · see citing works
Zhu, S., Zhuang, J., Wu, Q., Liu, Z., Liao, C., Luo, S., Chen, J., & Zhong, Z. (2018) · Aging Cell · doi:10.1111/acel.12764 · Cited by 55 · see citing works
Self-citationWu, Q., Zhong, Z., Zhu, S., et al. (2015) · APOPTOSIS · doi:10.1007/s10495-015-1191-4 · Cited by 54 · see citing works
Self-citationTao, L., Zhang, F., Hao, L., Wu, J., Jia, J., Liu, J., Zheng, L. T., & Zhen, X. (2014) · Journal of Pharmacological Sciences · doi:10.1254/jphs.14025fp · Cited by 42 · see citing works
Pasquali, L., Pecori, C., Lucchesi, C., LoGerfo, A., Iudice, A., Siciliano, G., & Bonuccelli, U. (2014) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2014.09.024 · Cited by 41 · see citing works
Ding, R., Jiang, H., Sun, B., Wu, X., Li, W., Zhu, S., Liao, C., Zhong, Z., & Chen, J. (2016) · Redox Biology · doi:10.1016/j.redox.2016.09.004 · Cited by 41 · see citing works
Self-citationLjubisavljević, S., Stojanović, I. R., Vojinović, S., et al. (2013) · Neurochemistry International · doi:10.1016/j.neuint.2013.02.025 · Cited by 37 · see citing works
Sparrey, C. J., Salegio, E. A., Camisa, W., et al. (2015) · Journal of Neurotrauma · doi:10.1089/neu.2015.3974 · Cited by 32 · see citing works
Conley, S., Abais‐Battad, J. M., Yuan, X., Zhang, Q., Boini, K., & Li, P.-L. (2017) · Free Radical Biology & Medicine · doi:10.1016/j.freeradbiomed.2017.02.027 · Cited by 24 · see citing works
Longitudinal electrophysiological changes after cervical hemi-contusion spinal cord injury in rats
Huang, Z., Li, R., Liu, J., et al. (2017) · Neuroscience Letters · doi:10.1016/j.neulet.2017.11.019 · Cited by 23 · see citing works
(2017) · Journal of Spinal Cord Medicine · doi:10.1080/10790268.2017.1294349 · Cited by 8 · see citing works
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Simpson, D. S. A., & Oliver, P. L. (2020) · Antioxidants · doi:10.3390/antiox9080743 · Cited by 1,044 · see citing works
“The mechanisms leading to ROS production and release by microglia have been explored, especially in CAA where NOX activation likely involves fibrin-related clotting factors and IL13 signalling [104,126].”
BackgroundInfluentialSu, Y., Liu, Y., He, D., Hu, G., Wang, H., Ye, B., He, Y., Gao, X., & Liu, D. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.108694 · Cited by 26 · see citing works
- Authors
- Liu, Z., Yao, X., Jiang, W., Li, W., Zhu, S., Liao, C., Zou, L., Ding, R., & Chen, J.
- Affiliations
- Nanfang Hospital (CN)
- Corresponding author
- Ding, Ruoting
- Chen, Jianting
- Venue
- Journal of Neuroinflammation
- Published
- 2020-03-20
- Volume
- 17
- Issue
- 1
- Pages
- 90-90
- ISSN
- 1742-2094 (ISSN-L)
- PMC
- PMC7082940
- OpenAlex
- W3012588800
- Cited by
- 430
- References
- 52
- Citations by year
- 2026: 57 · 2025: 94 · 2024: 107 · 2023: 75 · 2022: 64 · 2021: 22 · 2020: 11
- FWCI
- 28.27
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Neuroinflammation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (81772395)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Spinal Cord Injury Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- advanced oxidation protein products, spinal cord injury, microglial activation, neuroinflammation, oxidative stress, NADPH oxidase, reactive oxygen species, MAPK signaling, NF-κB, p38 MAPK, JNK, NLRP3 inflammasome, pyroptosis, gasdermin D, caspase-1, IL-1β, IL-18, apocynin, neuroprotection, biomarkers, functional recovery
- MeSH terms
- Pyroptosis, Animals, Cell Line, Inflammation, Male, Spinal Cord Injuries, NF-kappa B, Rats, Sprague-Dawley, Microglia, Oxidative Stress, MAP Kinase Signaling System, Mice, Rats, Advanced Oxidation Protein Products
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