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Inflammasomes in the CNS
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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“several inflammasomes have been characterized in microglia including NLRP1, NLRP3, and NLRC4 (Walsh et al, 2014).”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as Walsh et al, 2014
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“The NLRP3 inflammasome has been the most studied inflammasome in the CNS (Walsh et al, 2014)”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as Walsh et al, 2014
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“…in caspase-1 activation is the NLRP3 inflammasome, which contains an NLRP3 that recruits the ASC adaptor protein through its PYD domain, followed by caspase-1 binding to the ASC through its CARD domain (Lamkanfi and Dixit, 2012; Lamkanfi and Dixit, 2014; Walsh et al., 2014; Wen et al., 2013).”
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“The most intensively studied is the NLRP3 inflammasome which is formed when NLRP3 associates with the adaptor protein ASC and procaspase-1 upon activation by different stimuli, such as pathogen associated molecular patterns (PAMPs) or endogenous danger signals [9, 10].”
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“Studies have reported that impaired mitochondria and extracellular ATP may be key factors in triggering inflammasome formation in acute sterile brain injury (Walsh et al., 2014).”
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Focus on the Role of NLRP3 Inflammasome in Diseases
Fusco, R., Siracusa, R., Genovese, T., Cuzzocrea, S., & Paola, R. D. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21124223 · Cited by 301
Interleukin-1β Induces Blood–Brain Barrier Disruption by Downregulating Sonic Hedgehog in Astrocytes
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“NLRP1 & NLRP3) that form part of the inflammasome complex involved in activation of caspase-1, and the subsequent cleavage and release of IL-1β and IL-18 – another member of the IL-1 family (Rathinam et al., 2012; Walsh et al., 2014).”
BackgroundGlial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse
Lacagnina, M. J., Rivera, P. D., & Bilbo, S. D. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2016.121 · Cited by 271
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McKee, C. A., & Lukens, J. R. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00556 · Cited by 277
“Since the finding that inflammasome proteins are upregulated after TBI in human patients (98), significant attention has been paid to identify the inflammasome-associated signaling events that are engaged in response to brain trauma (14, 99, 100).”
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Panicker, N., Sarkar, S., Harischandra, D. S., Neal, M. P., Kam, T., Jin, H., Saminathan, H., Langley, M. R., Charli, A., Samidurai, M., et al. (2019) · The Journal of Experimental Medicine · doi:10.1084/jem.20182191 · Cited by 257
“Their assembly is triggered by a variety of stimuli and culminates in the activation of Casp-1, which then cleaves pro – IL-1 β to IL-1 β (Latz et al., 2013; Walsh et al., 2014).”
Inflammasome: Its role in traumatic brain and spinal cord injury
Mortezaee, K., Khanlarkhani, N., Beyer, C., & Zendedel, A. (2017) · Journal of Cellular Physiology · doi:10.1002/jcp.26287 · Cited by 255
“This state presumably assists rapid activation of the innate immune system after CNS injury (Walsh et al., 2014).”
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Zengeler, K. E., & Lukens, J. R. (2021) · Nature reviews. Immunology · doi:10.1038/s41577-020-00487-7 · Cited by 264
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“Moreover, DAMPs also bind to NLRs, which can activate inflammasome formation in microglia and macrophages, with subsequent IL-1β and IL-18 maturation (Gadani et al., 2015; Walsh et al., 2014).”
InfluentialYe, Y., Jin, T., Zhang, X. D., Zeng, Z. R., Ye, B., Wang, J., Zhong, Y., Xiong, X., & Gu, L. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00553 · Cited by 239
“Among these, NLRP3 is the most extensively studied in CNS diseases (Walsh et al., 2014).”
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Rapid inflammasome activation in microglia contributes to brain disease in HIV/AIDS
Walsh, J. G., Reinke, S. N., Mamik, M. K., McKenzie, B., Maingat, F. G., Branton, W. G., Broadhurst, D., & Power, C. (2014) · Retrovirology · doi:10.1186/1742-4690-11-35 · Cited by 236
“Inflammasome activation has been implicated in multiple infectious and immune diseases including those involving the brain [11-14].”
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Li, Y., Xia, Y., Yin, S., Wan, F., Hu, J., Kou, L., Sun, Y., Wu, J., Zhou, Q., Huang, J., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.719807 · Cited by 230
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A20 critically controls microglia activation and inhibits inflammasome-dependent neuroinflammation
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Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders
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Kuwar, R., Rolfe, A., Di, L., Xu, H., Liu, H., Jiang, Y., Zhang, S., & Sun, D. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1471-y · Cited by 208
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Araújo, B., Caridade-Silva, R., Soares-Guedes, C., Martins‐Macedo, J., Gomes, E. D., Monteiro, S., & Teixeira, F. G. (2022) · Cells · doi:10.3390/cells11182908 · Cited by 209
“Functionally, when facing pathogens, endogenous signals, aggregated substances (fibrillar α-Syn in microglia [90]) or when IL1β is secreted by microglia and sensed by NLRs, the ASC component is triggered [88,91].”
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“In addition, inflammasome activation especially the NLRP1 is under current investigation across a broad spectrum of neurological diseases, including infections, acute sterile brain injury and chronic neurodegenerative diseases [23].”
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“The microglial marker Iba-1, reactive oxygen species (ROS), nuclear factor kappa B (NF-κB) and key components of the NLRP3 inflammasome and its downstream inflammatory effectors (IL-1β and IL-18) were measured.”
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“The activation of the inflammasomes in the CNS are involved in the generation of an innate immune inflammatory response through IL-1β and IL-18 cytokine release and in cell death through the process of pyroptosis [108].”
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“IL-1 and IL-18 bind to their respective receptors—IL-1R1 and IL-18R—on microglial cells, astrocytes, neurons, and endothelial cells, triggering NF-κB-dependent transcriptional events, which result in the generation of multiple inflammationassociated genes [90].”
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“Despite strong evidence implicating multiple inflammasomes in CNS disease (90), there is no conclusive evidence describing pyroptosis within the brain.”
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“ment of a uniformly labeled 25 kDa protein: HET-s(1-227).”
BackgroundInflammasomes, hormesis, and antioxidants in neuroinflammation: Role of NRLP3 in Alzheimer disease
Pennisi, M., Crupi, R., Di Paola, R., Ontario, M. L., Bella, R., Calabrese, E. J., Crea, R., Cuzzocrea, S., & Calabrese, V. (2017) · Journal of Neuroscience Research · doi:10.1002/jnr.23986 · Cited by 157
“In addition, in response to pathogens or cellular stressors, such as pathological protein aggregates, ATP and ROS, microglia release excessive amount of proinflammatory cytokines (Walsh et al., 2014; Dilger and Johnson, 2008).”
BackgroundThe P2X7 Receptor Primes IL-1β and the NLRP3 Inflammasome in Astrocytes Exposed to Mechanical Strain
Albalawi, F., Lu, W., Beckel, J. M., Lim, J. C., McCaughey, S. A., & Mitchell, C. H. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00227 · Cited by 155
“…cytokines (Rathinam et al., 2012), and it has been implicated in neural disorders associated with mechanical strain or elevated pressure (Walsh et al., 2014), including traumatic brain injury, encephalitis, and glaucoma (Kaushik et al., 2012; Liu et al., 2013; Chi et al., 2014, 2015).”
BackgroundInflammasomes and human autoimmunity: A comprehensive review
Yang, C., & Chiang, B. (2015) · Journal of Autoimmunity · doi:10.1016/j.jaut.2015.05.001 · Cited by 161
Innate and adaptive immune responses in the CNS
Waisman, A., Liblau, R., & Becher, B. (2015) · The Lancet Neurology · doi:10.1016/s1474-4422(15)00141-6 · Cited by 158
Crowley, T., Cryan, J. F., Downer, E. J., & O’Leary, O. F. (2016) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2016.02.001 · Cited by 150
“…cell death known as pyroptotic cell death, shown to be a regulator of microglial cell survival 7 (Gustin et al., 2015) and having a role in inflammatory neuronal cell death, although the precise implications of inflammasome activation in the CNS remains relatively understudied (Walsh et al., 2014).”
BackgroundHaapakoski, R., Ebmeier, K. P., Alenius, H., & Kivimäki, M. (2016) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2015.11.012 · Cited by 157
“Initiation of an inflammatory response and the formation of the inflammasome enable the activation of proinflammatory caspases, mainly caspase-1 and subsequently, increased release of pro-inflammatory cytokines (Walsh et al., 2014).”
BackgroundLi, J., Xu, P., Hong, Y., Xie, Y., Peng, M., Sun, R., Guo, H., Zhang, X., Zhu, W., Wang, J., et al. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02819-5 · Cited by 153
“[39], and are involved in the initiation of the inflammatory response [40].”
BackgroundInflammation in Traumatic Brain Injury
Postolache, T. T., Wadhawan, A., Can, A., Lowry, C. A., Woodbury, M., Makkar, H., Hoisington, A. J., Scott, A. J., Potocki, E., Benros, M. E., et al. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-191150 · Cited by 154
“Multiple cells in the CNS —such as neurons, astrocytes, microglia, macrophages, and astrocytes—can contain assembled inflammasomes [115, 116], and levels of inflammasome proteins in the cerebrospinal fluid (CSF) generally predict a poorer outcome in TBI [117].”
Microglial inflammation and phagocytosis in Alzheimer's disease: Potential therapeutic targets
Nizami, S., Hall‐Roberts, H., Warrier, S., Cowley, S. A., & Di Daniel, E. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14618 · Cited by 147
“Active caspase‐1 cleaves pro‐IL‐1β and pro‐IL‐18 to mature IL‐1β and IL‐18, respectively, and these cytokines are released into the extracellular space by a nonconventional secretion pathway (de Rivero Vaccari et al., 2014; Walsh et al., 2014).”
BackgroundStress induced microglial activation contributes to depression
Li, B., Yang, W., Ge, T., Wang, Y., & Cui, R. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106145 · Cited by 151
Diet in Parkinson’s Disease: Critical Role for the Microbiome
Jackson, A., Forsyth, C. B., Shaikh, M., Voigt, R. M., Engen, P. A., Ramirez, V., & Keshavarzian, A. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.01245 · Cited by 145
“Inflammasomes are present in peripheral immune cells such as macrophages, as well as in the brain and especially in microglia (206, 210, 211).”
BackgroundExploring New Inflammatory Biomarkers and Pathways during LPS-Induced M1 Polarization
Cunha, C., Gomes, C., Vaz, A. R., & Brites, D. (2016) · Mediators of Inflammation · doi:10.1155/2016/6986175 · Cited by 153
“Inflamma-some mediators comprise NOD-like receptor family, pyrin domain containing 3 (NLRP3) and caspase-1 responsible for the cleavage of IL-18 and IL-1 𝛽 proforms [16].”
Neuroinflammatory responses in Alzheimer’s disease
Dansokho, C., & Heneka, M. T. (2017) · Journal of Neural Transmission · doi:10.1007/s00702-017-1831-7 · Cited by 146
“Activation of caspase-1 also results in a form of programmed cell death, known as pyroptosis (Venegas and Heneka 2017; Walsh et al. 2014).”
BackgroundQiu, J., Wang, M., Zhang, J., Cai, Q., Lu, D., Li, Y., Dong, Y., Zhao, T., & Chen, D. (2016) · International Immunopharmacology · doi:10.1016/j.intimp.2016.09.024 · Cited by 143
New Insights on NLRP3 Inflammasome: Mechanisms of Activation, Inhibition, and Epigenetic Regulation
Kodi, T., Sankhe, R., Gopinathan, A., Nandakumar, K., & Kishore, A. (2024) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-024-10101-5 · Cited by 157
“These express pattern recognition receptors (PRR) which are used to recognize PAMPs and DAMPs (Singhal et al. 2014; Walsh et al. 2014).”
BackgroundInhibition of the P2X7–PANX1 complex suppresses spreading depolarization and neuroinflammation
Chen, S., Qin, T., Seidel, J. L., Zheng, Y. Z., Eikermann, M., Ferrari, M. D., van den Maagdenberg, A. M. J. M., Moskowitz, M. A., Ayata, C., & Eikermann‐Haerter, K. (2017) · Brain · doi:10.1093/brain/awx085 · Cited by 137
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Neuroinflammation in neurological disorders: pharmacotherapeutic targets from bench to bedside
Mishra, A., Bandopadhyay, R., Singh, P. K., Mishra, P. S., Sharma, N., & Khurana, N. (2021) · Metabolic Brain Disease · doi:10.1007/s11011-021-00806-4 · Cited by 134
Crosstalk Between the Oxidative Stress and Glia Cells After Stroke: From Mechanism to Therapies
Zhu, G., Wang, X., Chen, L., Lenahan, C., Fu, Z., Fang, Y., & Yu, W. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.852416 · Cited by 138
Meng, X., Tan, L., Tan, M., Jiang, T., Tan, C., Li, M., Wang, H.-F., & Yu, J. (2014) · Journal of Neuroinflammation · doi:10.1186/s12974-014-0212-5 · Cited by 134
“It should be noted that, the high concentrations of extracellular ATP and K ions, and the generation of ROS are the most important factors for activating NLRP3 [37].”
Inflammasomes as therapeutic targets for A lzheimer's disease
White, C., Lawrence, C. B., Brough, D., & Rivers‐Auty, J. (2016) · Brain Pathology · doi:10.1111/bpa.12478 · Cited by 136
“Rodents express three paralogous NLRP1 genes where as humans only express one, and there are structural differences in the death domains (163).”
BackgroundInflammasome and α-synuclein in Parkinson's disease: A cross-sectional study
Chatterjee, K., Roy, A., Banerjee, R., Choudhury, S., Mondal, B., Halder, S., Basu, P., Shubham, S., Dey, S., & Kumar, H. (2019) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2019.577089 · Cited by 130
Activated protein C, protease activated receptor 1, and neuroprotection
Griffin, J. H., Zloković, B. V., & Mosnier, L. O. (2018) · Blood · doi:10.1182/blood-2018-02-769026 · Cited by 129
Yap, J. K. Y., Pickard, B. S., Chan, E. W. L., & Gan, S. Y. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-1638-7 · Cited by 130
“Several types of inflammasome have been identified within the central nervous system (CNS), of which the best characterized are the absent inmelanoma 2 (AIM2), NLR-family pyrin domain-containing 1 (NLRP1), NLRP3 and NLR-family CARD-containing 4 (NLRC4) inflammasomes [9].”
BackgroundAge-related cerebral small vessel disease and inflammaging
Li, T., Huang, Y., Cai, W., Chen, X., Men, X., Lü, T., Wu, A., & Lu, Z. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-03137-x · Cited by 128
Inflammasomes and autoimmune and rheumatic diseases: A comprehensive review
Shin, J. I., Lee, K. H., Joo, Y. H., Lee, J. M., Jeon, J., Jung, H. J., Shin, M., Cho, S., Kim, T.-H., Park, S., et al. (2019) · Journal of Autoimmunity · doi:10.1016/j.jaut.2019.06.010 · Cited by 125
Chang, Y., Zhu, J., Wang, D., Li, H., He, Y., Liu, K., Wang, X., Peng, Y., Pan, S., & Huang, K. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01879-1 · Cited by 123
Lammerding, L., Slowik, A., Johann, S., Beyer, C., & Zendedel, A. (2015) · Neuroendocrinology · doi:10.1159/000439435 · Cited by 123
Neuroinflammatory changes negatively impact on LTP: A focus on IL-1β
Lynch, M. A. (2015) · Brain Research · doi:10.1016/j.brainres.2014.08.040 · Cited by 115
“…1, is triggered by activation of members of the mammalian nucleotide binding domain, leucine-rich repeat (LRR)-containing receptor (NLR) family and results in activation of caspase 1 with the subsequent processing and release of IL-1β and IL-18 (Tschopp et al., 2003; Walsh et al., 2014).”
InfluentialEstrogen Attenuates Local Inflammasome Expression and Activation after Spinal Cord Injury
Zendedel, A., Mönnink, F., Hassanzadeh, G., Zaminy, A., Ansar, M. M., Habib, P., Slowik, A., Kipp, M., & Beyer, C. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0400-2 · Cited by 119
“How the inflammasomes are activated is still debated, but in the case of NLRP3, which is the most studied caspase-1 activator [47], several signals related to cell damage and stress such as generation of extracellular ATP, production of reactive oxygen species (ROS), and activators that form crystalline/particulate li…”
NADPH Oxidase 2 Regulates NLRP3 Inflammasome Activation in the Brain after Traumatic Brain Injury
Ma, M. W., Wang, J., Dhandapani, K. M., & Brann, D. W. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/6057609 · Cited by 118
Modulation of microglia polarization dynamics during diabetic retinopathy in db / db mice
Arroba, A. I., Alcalde‐Estévez, E., García‐Ramírez, M., Cazzoni, D., de la Villa, P., Sánchez‐Fernández, E. M., Mellet, C. O., Fernández, J. M. G., Hernández, C., Simó, R., et al. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2016.05.024 · Cited by 115
High resolution dissection of reactive glial nets in Alzheimer’s disease
Bouvier, D. S., Jones, E. V., Quesseveur, G., Davoli, M. A., A. Ferreira, T., Quirion, R., Mechawar, N., & Murai, K. K. (2016) · Scientific Reports · doi:10.1038/srep24544 · Cited by 111
Microglial CMPK2 promotes neuroinflammation and brain injury after ischemic stroke
Guan, X., Zhu, S., Song, J.-Q., Liu, K., Liu, M., Xie, L., Wang, Y., Wu, J. S., Xu, X., & Pang, T. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101522 · Cited by 114
Metadata
- Authors
- Walsh, J. G., Muruve, D. A., & Power, C.
- Affiliations
- University of Alberta (CA)
- University of Calgary (CA)
- Corresponding author
- Power, Christopher
- Venue
- Nature Reviews Neuroscience
- Published
- 2014-01-08
- Volume
- 15
- Issue
- 2
- Pages
- 84-97
- ISSN
- 1471-003X (ISSN-L)
- 1471-0048
- 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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