Cited by 641Inflammasome and immune disordersNeuroinflammation and Neurodegeneration MechanismsImmune Response and Inflammation

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Inflammasomes in the CNS

Walsh, John G., Muruve, Daniel A., Power, Christopher·2014·Nature Reviews Neuroscience

DOI 10.1038/nrn3638

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Abstract

Microglia and macrophages in the CNS contain multimolecular complexes termed inflammasomes. Inflammasomes function as intracellular sensors for infectious agents as well as for host-derived danger signals that are associated with neurological diseases, including meningitis, stroke and Alzheimer's disease. Assembly of an inflammasome activates caspase 1 and, subsequently, the proteolysis and release of the cytokines interleukin-1β and interleukin-18, as well as pyroptotic cell death. Since the discovery of inflammasomes in 2002, there has been burgeoning recognition of their complexities and functions. Here, we review the current understanding of the functions of different inflammasomes in the CNS and their roles in neurological diseases.

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“have showed inflammasome formation in different neuronal disorders including SCI [12, 21, 38, 45].”
Nonessential Role for the NLRP1 Inflammasome Complex in a Murine Model of Traumatic Brain Injury
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ER-mitochondria communication is involved in NLRP3 inflammasome activation under stress conditions in the innate immune system
Pereira, A. C., Pascale, J. D., Resende, R., Cardoso, S., Ferreira, I., Neves, B. M., Carrascal, M. A., Zuzarte, M., Madeira, N. G. G. F., Morais, S., et al. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04211-7 · Cited by 81
“It is mainly caused by the activation of microglia, the primary resident innate immune cells in the CNS able to trigger an immunologic response [18].”
BackgroundInfluential
Interleukin-1 β-Targeted Treatment Strategies in Inflammatory Depression: Toward Personalized Care
Ellul, P., Boyer, L., Groc, L., Leboyer, M., & Fond, G. (2016) · Acta Psychiatrica Scandinavica · doi:10.1111/acps.12656 · Cited by 65
Neuronal Damage and Neuroinflammation, a Bridge Between Bacterial Meningitis and Neurodegenerative Diseases
Farmen, K., Tofiño-Vian, M., & Iovino, F. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.680858 · Cited by 73
“is considered a promising target in the context of bacterial meningitis (Walsh et al., 2014) and neurodegenerative diseases (Heneka et al.”
Background
The NLRP3 inflammasome modulates sleep and NREM sleep delta power induced by spontaneous wakefulness, sleep deprivation and lipopolysaccharide
Zielinski, M. R., Gerashchenko, D., Karpova, S. A., Konanki, V., McCarley, R. W., Sutterwala, F. S., Strecker, R. E., & Basheer, R. (2017) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2017.01.012 · Cited by 73
Andrographolide ameliorates intracerebral hemorrhage induced secondary brain injury by inhibiting neuroinflammation induction
Li, X., Wang, T., Zhang, D., Li, H., Shen, H., Ding, X., & Chen, G. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.09.015 · Cited by 70
“The innate immune system of the central nervous system (CNS) includes microglia, macrophages and astrocytes; microglia play a critical role as they can control pathological processes and maintain CNS homeostasis (Suzumura, 2017; Walsh et al., 2014; Xi et al., 2006).”
5-(3,4-Difluorophenyl)-3-(6-methylpyridin-3-yl)-1,2,4-oxadiazole (DDO-7263), a novel Nrf2 activator targeting brain tissue, protects against MPTP-induced subacute Parkinson's disease in mice by inhibiting the NLRP3 inflammasome and protects PC12 cells against oxidative stress
Xu, L., Wu, Y., Yan, F., Li, C., Dai, Z., You, Q., Jiang, Z., & Di, B. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.01.003 · Cited by 70
LncRNA 4344 promotes NLRP3-related neuroinflammation and cognitive impairment by targeting miR‐138-5p
Feng, X., Zhan, F., Luo, D., Hu, J., Wei, G., Hua, F., & Xu, G. (2021) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2021.08.230 · Cited by 66
Inflammation: Bridging Age, Menopause and APOEε4 Genotype to Alzheimer’s Disease
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“It can detect a wide range of metabolic and aging-related DAMPS, such as ROS production, glucose tolerance, and insulin resistance (Vandanmagsar et al., 2011; Salminen et al., 2012; Walsh et al., 2014), lipotoxic fatty acids, ceramides, free cholesterol, uric acid, and ATP, and it releases IL-1β and IL-18 (Youm et al.”
Background
Echinacoside protects dopaminergic neurons by inhibiting NLRP3/Caspase-1/IL-1β signaling pathway in MPTP-induced Parkinson’s disease model
Gao, M.-R., Wang, M., Jia, Y., Tian, D., Liu, A., Wang, W.-J., Yang, L., Chen, J., Yang, Q., Liu, R., et al. (2020) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2020.08.015 · Cited by 69
Noncanonical Pyroptosis Triggered by Macrophage‐Derived Extracellular Vesicles in Chondrocytes Leading to Cartilage Catabolism in Osteoarthritis
Ebata, T., Terkawi, M. A., Kitahara, K., Yokota, S., Shiota, J., Nishida, Y., Matsumae, G., Alhasan, H., Hamasaki, M., Hontani, K., et al. (2023) · Arthritis & Rheumatology · doi:10.1002/art.42505 · Cited by 69
P2Y12Receptor on the Verge of a Neuroinflammatory Breakdown
Amadio, S., Parisi, C., Montilli, C., Carrubba, A. S., Apolloni, S., & Volonté, C. (2014) · Mediators of Inflammation · doi:10.1155/2014/975849 · Cited by 73
Zika virus induces inflammasome activation in the glial cell line U87-MG
Tricarico, P. M., Caracciolo, I., Crovella, S., & D’Agaro, P. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.01.158 · Cited by 70
Effective Modulation of CNS Inhibitory Microenvironment using Bioinspired Hybrid‐Nanoscaffold‐Based Therapeutic Interventions
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Blood‒Brain Barrier Pathology and CNS Outcomes in Streptococcus pneumoniae Meningitis
Yau, B., Hunt, N. H., Mitchell, A. J., & Too, L. K. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19113555 · Cited by 72
“In addition to TLRs, NLRs localise within the cytosol, alongside pyrin and hematopoietic interferon-inducible nuclear antigens with a 200-amino-acid repeat (HIN) domain-containing proteins (PYHIN), to sense intracellular PAMPs and DAMPs (reviewed in [102]).”
Background
Surface-fill H2S-releasing silk fibroin hydrogel for brain repair through the repression of neuronal pyroptosis
Chen, X., Huang, X., Liu, C., Li, S., Yang, Z., Zhang, F., Chen, X., Shan, H., Tao, L., & Zhang, M. (2022) · Acta Biomaterialia · doi:10.1016/j.actbio.2022.11.021 · Cited by 67
Aging with HIV infection: A journey to the center of inflammAIDS, immunosenescence and neuroHIV
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Inflammasome Involvement in Alzheimer’s Disease
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“Inflammation in the CNS can have both pathological and protective effects depending on the biological circumstances [28].”
Tetrahydroxy stilbene glycoside alleviated inflammatory damage by mitophagy via AMPK related PINK1/Parkin signaling pathway
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Administration of 17β-Estradiol Improves Motoneuron Survival and Down-regulates Inflammasome Activation in Male SOD1(G93A) ALS Mice
Heitzer, M., Kaiser, S., Kanagaratnam, M., Zendedel, A., Hartmann, P., Beyer, C., & Johann, S. (2017) · Molecular Neurobiology · doi:10.1007/s12035-016-0322-4 · Cited by 69
“NLRP3 is by far the most studied inflammasome and implicated in various neurological diseases [10].”
miR‐29c‐3p inhibits microglial NLRP3 inflammasome activation by targeting NFAT5 in Parkinson's disease
Wang, R., Li, Q., He, Y., Yang, Y., Ma, Q., & Li, C. (2020) · Genes to Cells · doi:10.1111/gtc.12764 · Cited by 64
17β-Estradiol Regulates Microglia Activation and Polarization in the Hippocampus Following Global Cerebral Ischemia
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“Inflammation in the central nervous system involves responses from resident immune cells, microglia, inflammasomes, and downstream inflammatory cytokine production [39, 40].”
Background
Pyruvate kinase M2 (PKM2) interacts with activating transcription factor 2 (ATF2) to bridge glycolysis and pyroptosis in microglia
Li, M., Lu, H., Wang, X., Duan, C., Zhu, X., Zhang, Y., Ge, X., Ji, F., Wang, X., Su, J., et al. (2021) · Molecular Immunology · doi:10.1016/j.molimm.2021.10.017 · Cited by 60
Interleukin-4 receptor signaling modulates neuronal network activity
Hanuscheck, N., Thalman, C., Domingues, M., Schmaul, S., Muthuraman, M., Hetsch, F., Ecker, M., Endle, H., Oshaghi, M., Martino, G., et al. (2022) · The Journal of Experimental Medicine · doi:10.1084/jem.20211887 · Cited by 61
“Furthermore, glia-derived TNF α was demonstrated to mediate homeostatic synaptic scaling (Stellwagen and Malenka, 2006), and in Caenorhabditis elegans neuronal IL-17 signaling was shown to play a regulatory role in escape behavior and associative learning (Flynn et al., 2020).”
Influential
Microglial Activation in Metal Neurotoxicity: Impact in Neurodegenerative Diseases
Martínez-Hernández, M. I., Acosta‐Saavedra, L. C., Hernández‐Kelly, L. C., Loaeza‐Loaeza, J., & Ortega, A. (2023) · BioMed Research International · doi:10.1155/2023/7389508 · Cited by 63
NLRP3 Inflammasome’s Activation in Acute and Chronic Brain Diseases—An Update on Pathogenetic Mechanisms and Therapeutic Perspectives with Respect to Other Inflammasomes
Chiarini, A., Gui, L., Viviani, C., Armato, U., & Prà, I. D. (2023) · Biomedicines · doi:10.3390/biomedicines11040999 · Cited by 62
Ginsenoside Rg1 alleviates chronic inflammation-induced neuronal ferroptosis and cognitive impairments via regulation of AIM2 - Nrf2 signaling pathway
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IRE1α inhibition attenuates neuronal pyroptosis via miR-125/NLRP1 pathway in a neonatal hypoxic-ischemic encephalopathy rat model
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“NLRP1 was the first inflammasome to be characterized and was reported to promote pyroptosis in neurons [22, 46].”
BackgroundInfluential
Pharmacologic inhibition of NLRP3 reduces the levels of α-synuclein and protects dopaminergic neurons in a model of Parkinson’s disease
Amo‐Aparicio, J., Daly, J., Højen, J. F., & Dinarello, C. A. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02830-w · Cited by 67
“As it has been previously described, the NLRP3 inflammasome is linked to microglia-mediated inflammation in PD [52, 53].”
Background
The intrinsic pathogenic role of autoantibodies to aquaporin 4 mediating spinal cord disease in a rat passive-transfer model
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“, 2008) or (2) a consequence of complex neuroinflammatory signalling by microglia or activated astrocytes (Graeber, 2010; Prinz and Priller, 2014; Walsh et al., 2014).”
Background
Actin dynamics shape microglia effector functions.
Uhlemann, R., Gertz, K., Boehmerle, W., Schwarz, T., Nolte, C., Freyer, D., Kettenmann, H., Endres, M., & Kronenberg, G. (2016) · Brain Structure and Function · doi:10.1007/s00429-015-1067-y · Cited by 61
Harnessing Microglia and Macrophages for the Treatment of Glioblastoma
Prionisti, I., Bühler, L. H., Walker, P. R., & Jolivet, R. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00506 · Cited by 63
“Activation of NLRP3, followed by activation of Caspase-1, results in the production and release of interleukin-1β (IL-1β) and interleukin18 (IL-18) (Walsh et al., 2014; Wolf et al., 2017).”
Background
Inhibition of caspase-1-mediated inflammasome activation reduced blood coagulation in cerebrospinal fluid after subarachnoid haemorrhage
Fang, Y., Wang, X., Lü, J., Shi, H. R., Huang, L., Shao, A., Zhang, A., Liu, Y., Ren, R., Lenahan, C., et al. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2022.103843 · Cited by 58
Methamphetamine abuse affects gene expression in brain-derived microglia of SIV-infected macaques to enhance inflammation and promote virus targets
Najera, J. A., Bustamante, E., Bortell, N., Morsey, B., Fox, H. S., Ravasi, T., & Marcondes, M. C. G. (2016) · BMC Immunology · doi:10.1186/s12865-016-0145-0 · Cited by 57
“PYCARD is one of the components of the inflammasome, which is potentially activated by TLR-mediated viral recognition signaling pathways that enhance the inflammatory environment in the CNS [63–65].”
NLRP3 inflammasome activates interleukin-23/interleukin-17 axis during ischaemia-reperfusion injury in cerebral ischaemia in mice
Wang, H., Zhong, D., Chen, H., Jin, J., Liu, Q., & Li, G. (2019) · Life Sciences · doi:10.1016/j.lfs.2019.04.031 · Cited by 58
Targeting NLRP3 Inflammasome in Translational Treatment of Nervous System Diseases: An Update
Yu, Q., Zhao, T., Liu, M., Cao, D., Li, J., Li, Y., Xia, M., Wang, X., Zheng, T., Liu, C., et al. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.707696 · Cited by 61
“Microglia, which first appear around hematoma, are important immune cells of the central nervous system and mainly participate in the central nervous system’s innate immune response (Walsh et al., 2014).”
Background
Targeting the NLRP3 Inflammasome in Neuroinflammation: Health Promoting Effects of Dietary Phytochemicals in Neurological Disorders
Hung, W., Ho, C., & Pan, M. (2019) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201900550 · Cited by 57
Role of Glia in the Regulation of Sleep in Health and Disease
Garofalo, S., Picard, K., Limatola, C., Nadjar, A., Pascual, O., & Tremblay, M. (2020) · Comprehensive physiology · doi:10.1002/cphy.c190022 · Cited by 64
“Using NLRP3 knockout mice, they demonstrated a lack of NREM sleep increase in response to the endotoxin, indicating that the NLRP3 inflammasome, which is found in neurons and glial cells, is involved in sleep modulation, likely via the production of IL-1 β (123, 345, 363).”
Transforming growth factor-β1 protects against LPC-induced cognitive deficit by attenuating pyroptosis of microglia via NF-κB/ERK1/2 pathways
Xie, Y., Chen, X., Li, Y., Chen, S., Liu, S., Yu, Z., & Wang, W. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02557-0 · Cited by 57
“Inflammasome activation and pyroptosis have been reported existing in multiple cell types in CNS [68].”
BackgroundInfluential
NLRP3 inflammasome deficiency attenuates cerebral ischemia-reperfusion injury by inhibiting ferroptosis
Wang, Z., Li, Y., Ye, Y., Zhu, H., Zhang, J., Wang, H., Lei, J., Gu, L., & Zhan, L. (2022) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2022.11.016 · Cited by 60
Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis
Oussini, H. E., Bayer, H., Scekic‐Zahirovic, J., Vercruysse, P., Sinniger, J., Dirrig‐Grosch, S., Dieterle, S., Echaniz‐Laguna, A., Larmet, Y., Müller, K., et al. (2016) · Acta Neuropathologica · doi:10.1007/s00401-016-1534-4 · Cited by 62
“1 3 relationships between microglial activation, for instance through inflammasomes [70], and microglial survival are not understood.”
Background
Elongator mutation in mice induces neurodegeneration and ataxia-like behavior
Kojic, M., Gaik, M., Kiska, B., Salerno-Kochan, A., Hunt, S., Tedoldi, A., Mureev, S., Jones, A., Whittle, B., Genovesi, L. A., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05765-6 · Cited by 56
Gasdermin Family: a Promising Therapeutic Target for Stroke
Chen, S., Mei, S., Luo, Y., Wu, H., Zhang, J., & Zhu, J. (2018) · Translational Stroke Research · doi:10.1007/s12975-018-0666-3 · Cited by 58
ATP and potassium ions: a deadly combination for astrocytes
Jackson, D. G., Wang, J., Keane, R. W., Scemes, E., & Dahl, G. (2014) · Scientific Reports · doi:10.1038/srep04576 · Cited by 55

Authors: Walsh, J. G., Muruve, D. A., & Power, C.
Affiliations: University of Alberta (CA)
University of Calgary (CA)
Corresponding author: Power, Christopher
ORCID: Muruve, Daniel A.
Power, Christopher
Venue: Nature Reviews Neuroscience
Publisher: Springer Science and Business Media LLC
Published: 2014-01-08
Volume: 15
Issue: 2
Pages: 84-97
ISSN: 1471-003X (ISSN-L)
1471-0048
DOI: 10.1038/nrn3638
OpenAlex: W1981649246
Cited by: 637
References: 149
Citations by year: 2026: 25 · 2025: 18 · 2024: 46 · 2023: 49 · 2022: 77 · 2021: 67 · 2020: 76 · 2019: 58 · 2018: 51 · 2017: 47 · 2016: 57 · 2015: 43 · 2014: 22
FWCI: 5.34
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature reviews. Neuroscience (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords: inflammasome, central nervous system, caspase-1, IL-1β, IL-18, pyroptosis, microglia, macrophages, neurological disorders, meningitis, stroke, Alzheimer's disease, innate immunity, damage-associated molecular patterns
MeSH terms: Animals, Central Nervous System, Humans, Macrophages, Nervous System Diseases, Neuroglia, Inflammasomes

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