Targeting NLRP3 Inflammasome in Translational Treatment of Nervous System Diseases: An Update

Neuroinflammatory response is the immune response mechanism of the innate immune system of the central nervous system. Both primary and secondary injury can activate neuroinflammatory response. Among them, the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome plays a key role in the inflammatory response of the central system. Inflammasome is a type of pattern recognition receptor, a cytoplasmic polyprotein complex composed of members of the Nod-like receptor (NLR) family and members of the pyrin and HIN domain (PYHIN) family, which can be affected by a variety of pathogen-related molecular patterns or damage-related molecular patterns are activated. As one of the research hotspots in the field of medical research in recent years, there are increasing researches on immune function abnormalities in the onset of neurological diseases such as depression, AD, ischemic brain injury and cerebral infarction, the NLRP3 inflammasome causes the activated caspase-1 to cleave pre-interleukin-1β and pre-interleukin-18 into mature interleukin-1β and interleukin-18, in turn, a large number of inflammatory factors are produced, which participate in the occurrence and development of the above-mentioned diseases. Targeted inhibition of the activation of inflammasomes can reduce the inflammatory response, promote the survival of nerve cells, and achieve neuroprotective effects. This article reviews NLRP3 inflammasome’s role in neurological diseases and related regulatory mechanisms, which providing references for future research in this field.

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By Regulating the NLRP3 Inflammasome Can Reduce the Release of Inflammatory Factors in the Co-Culture Model of Tuberculosis H37Ra Strain and Rat Microglia

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.637769 ◽

2021 ◽

Vol 11 ◽

Author(s):

Zhen Xie ◽

Hao Hui ◽

Qian Yao ◽

Yan Duan ◽

Wu Li ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Inflammatory Response ◽

Nlrp3 Inflammasome ◽

Tuberculosis Infection ◽

Inflammatory Factors ◽

Regulation Mechanism ◽

High Potassium ◽

Culture Model ◽

The Central Nervous System

ObjectiveTuberculosis infection of the Central Nervous System can cause severe inflammation in microglia, and NLRP3 inflammasome is also an important source of inflammation in microglia. Therefore, in this study, we used a co-culture model of rat microglia and tuberculosis H37Ra strain to explore the influence of tuberculosis infection on the NLRP3 inflammasome in microglia and its regulation mechanism.MethodsWe cultured primary microglia from SD rats and co-cultured with tuberculosis H37Ra strain for 4 hours to establish a co-culture model. At the same time, MCC950, Z-YVAD-FMK, BAY-11-7082, Dexamethasone, RU486, BzATP, BBG and extracellular high potassium environment were used to intervene the co-cultivation process. Subsequently, western blot, real-time PCR, ELISA and other methods were used to detect the changes of NLRP3 inflammasome-related molecules in microglia.ResultsAfter co-cultivation, the NLRP3 inflammasomes in microglia were activated and released a large amount of IL-18 and IL-1β. By regulating NLRP3 inflammasome complex, caspase-1, NF-κB and P2X7R during the co-culture process, it could effectively reduce the release of IL-18 and IL-1β, and the mortality of microglia.ConclusionOur results indicate that the NLRP3 inflammasome pathway is an important part of the inflammatory response of microglia caused by tuberculosis infection. By intervening the NLRP3 inflammasome pathway, it can significantly reduce the inflammatory response and mortality of microglia during the tuberculosis H37Ra strain infection. This research can help us further understand the inflammatory response mechanism of the central nervous system during tuberculosis infection and improve its treatment.

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NLRC4 Mutation in flagellin-derived peptide CBLB502 ligand-binding domain reduces the inflammatory response but not radioprotective activity

Journal of Radiation Research ◽

10.1093/jrr/rrz062 ◽

2019 ◽

Vol 60 (6) ◽

pp. 780-785

Author(s):

Lili Lai ◽

Ganggang Yang ◽

Xuelian Yao ◽

Lei Wang ◽

Yiqun Zhan ◽

...

Keyword(s):

Inflammatory Response ◽

Nuclear Factor Kappa B ◽

Binding Domain ◽

Receptor Protein ◽

Toll Like Receptor ◽

Interleukin 18 ◽

Radioprotective Activity ◽

Binding Domains ◽

Molecular Pattern ◽

Toll Like Receptor 5

ABSTRACT Bacterial flagellin is a pathogen-associated molecular pattern recognized by surface-localized Toll-like receptor 5 (TLR5) and cytosolic NOD-like receptor protein 4 (NLRC4). CBLB502, derived from Salmonella flagellin, exhibits high radioprotective efficacy in mice and primates by regulating TLR5 and the nuclear factor kappa B (NF-κB) signaling pathway. In this study, we examined the effects of CBLB502 and mutations in its NLRC4- and TLR5-binding domains on radioprotective efficacy and the immune inflammatory response. The results showed that CBLB502 mutation with I213A in the TLR5-binding domain significantly reduced NF-κB activity and radioprotective activity, whereas CBLB502 mutation with L292A in NLRC4-binding domain did not. Additionally, CBLB502 with both mutations greatly reduced NF-κB activity and eliminated radioprotection in mice. In contrast, NLRC4-binding domain mutation reduced the secretion of inflammatory interleukin-1β and interleukin-18. CBLB502 exerts its radioprotective effects through both the TLR5 and NLRC4 pathways. Additionally, deletion in the NLRC4-binding domain did not reduce radioprotective activity but reduced the inflammatory response.

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Inflammatory Cytokine Profile and Plasticity of Brain and Spinal Microglia in Response to ATP and Glutamate

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.634020 ◽

2021 ◽

Vol 15 ◽

Author(s):

Sam Joshva Baskar Jesudasan ◽

Somnath J. Gupta ◽

Matthew A. Churchward ◽

Kathryn G. Todd ◽

Ian R. Winship

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Interleukin 1 ◽

Inflammatory Factors ◽

Surrounding Environment ◽

Glial Cultures ◽

Inflammatory Phenotype ◽

The Central Nervous System ◽

Molecular Patterns

Microglia are the primary cells in the central nervous system that identify and respond to injury or damage. Such a perturbation in the nervous system induces the release of molecules including ATP and glutamate that act as damage-associated molecular patterns (DAMPs). DAMPs are detected by microglia, which then regulate the inflammatory response in a manner sensitive to their surrounding environment. The available data indicates that ATP and glutamate can induce the release of pro inflammatory factors TNF (tumor necrosis factor), IL-1β (interleukin 1 beta), and NO (nitric oxide) from microglia. However, non-physiological concentrations of ATP and glutamate were often used to derive these insights. Here, we have compared the response of spinal cord microglia (SM) relative to brain microglia (BM) using physiologically relevant concentrations of glutamate and ATP that mimic injured conditions in the central nervous system. The data show that ATP and glutamate are not significant modulators of the release of cytokines from either BM or SM. Consistent with previous studies, spinal microglia exhibited a general trend toward reduced release of inflammatory cytokines relative to brain-derived microglia. Moreover, we demonstrate that the responses of microglia to these DAMPs can be altered by modifying the biochemical milieu in their surrounding environment. Preconditioning brain derived microglia with media from spinal cord derived mixed glial cultures shifted their release of IL-1ß and IL-6 to a less inflammatory phenotype consistent with spinal microglia.

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Inflammatory cytokine profile and plasticity of brain and spinal microglia in response to ATP and glutamate

10.1101/2020.11.02.365676 ◽

2020 ◽

Author(s):

Sam Joshva Baskar Jesudasan ◽

Somnath J Gupta ◽

Matthew A Churchward ◽

Kathryn Todd ◽

Ian R Winship

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Interleukin 1 ◽

Inflammatory Factors ◽

Surrounding Environment ◽

Glial Cultures ◽

Inflammatory Phenotype ◽

The Central Nervous System ◽

Molecular Patterns

AbstractMicroglia are the primary cells in the central nervous system that identify and respond to injury or damage. Such a perturbation in the nervous system induces the release of molecules including ATP and glutamate that act as damage-associated molecular patterns (DAMPs). DAMPs are detected by microglia, which then regulate the inflammatory response in a manner sensitive to their surrounding environment. The available data indicates that ATP and glutamate can induce the release of pro inflammatory factors TNF (tumor necrosis factor), IL-1β (interleukin 1 beta) and NO (nitric oxide) from microglia. However, non-physiological concentrations of ATP and glutamate were often used to derive these insights. Here, we have compared the response of spinal cord microglia (SM) relative to brain microglia (BM) using physiologically relevant concentrations of glutamate and ATP that mimic injured conditions in the central nervous system. The data show that ATP and glutamate are not significant modulators of the release of cytokines from either BM or SM. Consistent with previous studies, spinal microglia exhibited a general trend towards reduced release of inflammatory cytokines relative to brain-derived microglia. Moreover, we demonstrate that the responses of microglia to these DAMPs can be altered by modifying the biochemical milieu in their surrounding environment. Preconditioning brain derived microglia with media from spinal cord derived mixed glial cultures shifted their release of IL-ß, IL-6 and IL-10 to a less inflammatory phenotype consistent with a spinal microglia.

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Pharmacological Inhibition of BTK reduces neuroinflammation and stress induced anxiety in vivo

10.1101/2021.01.11.426241 ◽

2021 ◽

Author(s):

Simantini Ghosh ◽

Zaidan Mohammed ◽

Itender Singh

Keyword(s):

Inflammatory Response ◽

Nlrp3 Inflammasome ◽

Therapeutic Potential ◽

Inflammasome Activation ◽

Neuroinflammatory Response ◽

Pharmacological Inhibition ◽

Nlrp3 Inflammasome Activation ◽

Human Stress ◽

Anxious Behavior

AbstractStress related disorders lead to serious psychiatric disabilities and are comorbid with anxiety and depression. Current therapies targeting several neurotransmitter systems are only able to mitigate symptoms partially. It is well recognized that stress and trauma related disorders lead to a prominent inflammatory response in humans, and in several animal models a robust neuroinflammatory response has been observed. However, the therapeutic potential of targeting specific components of the inflammatory response has not been adequately studied in this context. The current study investigated the NLRP3 - Caspase1-IL-1β pathway, which recent research has identified as a major contributor to exacerbated inflammatory response in several peripheral and central nervous system pathological conditions. Using two different models of stress, first - single prolonged restraint stress followed by brief underwater submersion and second - predator odor exposure in mice, we demonstrate heightened anxious behavior in mice one-week after stress. Females in both models display an exacerbated anxiety response than males within the stressed group. Consistent with this data stressed animals demonstrate upregulation of IL-1β, IL-6, Caspase1 activity and NLRP3 inflammasome activation in brain, with female animals showing a stronger neuroinflammatory phenotype. Pharmacological inhibition of NLRP3 inflammasome activation led to a rescue in terms of anxious behavior as well as attenuated neuroinflammatory response, both of which were significantly more prominent in female animals. Further, we observed induction of activated Bruton’s Tyrosine Kinase (BTK), an upstream positive regulator of NLRP3 inflammasome activation, in hippocampus and amygdala of stressed mice. Next, we conducted proof-of-concept pharmacological BTK inhibitor studies with Ibrutinib, a drug that is already FDA approved for use in certain types of lymphomas and leukemias, as well as a second inhibitor of BTK, LFM-A13. In both sets of experiments, we found inhibition of BTK significantly reduced the anxious behavior in stressed mice and attenuated the induction of NLRP3 inflammasome, Caspase 1 and IL1β. Our results suggest that BTK inhibition can be further investigated in context of human stress and trauma related disorders as a therapeutic strategy.

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The Role of the Effects of Autophagy on NLRP3 Inflammasome in Inflammatory Nervous System Diseases

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.657478 ◽

2021 ◽

Vol 9 ◽

Author(s):

Shizhen Zhao ◽

Xiaotian Li ◽

jie Wang ◽

Honggang Wang

Keyword(s):

Nervous System ◽

Nlrp3 Inflammasome ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Cerebral Hypoperfusion ◽

Receptor Protein ◽

Future Research ◽

Nervous System Diseases ◽

Caspase 1

Autophagy is a stable self-sustaining process in eukaryotic cells. In this process, pathogens, abnormal proteins, and organelles are encapsulated by a bilayer membrane to form autophagosomes, which are then transferred to lysosomes for degradation. Autophagy is involved in many physiological and pathological processes. Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome, containing NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and pro-caspase-1, can activate caspase-1 to induce pyroptosis and lead to the maturation and secretion of interleukin-1 β (IL-1 β) and IL-18. NLRP3 inflammasome is related to many diseases. In recent years, autophagy has been reported to play a vital role by regulating the NLRP3 inflammasome in inflammatory nervous system diseases. However, the related mechanisms are not completely clarified. In this review, we sum up recent research about the role of the effects of autophagy on NLRP3 inflammasome in Alzheimer’s disease, chronic cerebral hypoperfusion, Parkinson’s disease, depression, cerebral ischemia/reperfusion injury, early brain injury after subarachnoid hemorrhage, and experimental autoimmune encephalomyelitis and analyzed the related mechanism to provide theoretical reference for the future research of inflammatory neurological diseases.

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Residual inflammatory risk associated with interleukin-18 and interleukin-6 after successful interleukin-1β inhibition with canakinumab: further rationale for the development of targeted anti-cytokine therapies for the treatment of atherothrombosis

European Heart Journal ◽

10.1093/eurheartj/ehz542 ◽

2019 ◽

Vol 41 (23) ◽

pp. 2153-2163 ◽

Cited By ~ 26

Author(s):

Paul M Ridker ◽

Jean G MacFadyen ◽

Tom Thuren ◽

Peter Libby

Keyword(s):

Nlrp3 Inflammasome ◽

Interleukin 6 ◽

Recurrent Events ◽

Interleukin 1Β ◽

Dependent Manner ◽

Interleukin 18 ◽

Vascular Events ◽

P Values ◽

All Cause Mortality ◽

Increase In Risk

Abstract Aims The Canakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS) established that targeting inflammation with interleukin-1β (IL-1β) inhibition can significantly reduce cardiovascular (CV) event rates in the absence of any beneficial effects on cholesterol. Yet, CANTOS participants treated with both high-intensity statins and canakinumab remain at considerable risk for recurrent CV events. Both interleukin-18 (IL-18, which like IL-1β requires the NLRP3 inflammasome for activation) and interleukin-6 (IL-6, a pro-inflammatory cytokine downstream of IL-1) may contribute to the recurrent events that occur even on canakinumab therapy, and thus represent novel targets for treating atherothrombosis. Methods and results Plasma samples from 4848 stable post-myocardial infarction patients who were assigned to active IL-1β inhibition or placebo within CANTOS underwent measurement of IL-18 and IL-6 both before and after initiation of canakinumab using validated ELISA. All participants were followed over a median 3.7-year period (maximum 5 years) for recurrent major adverse cardiovascular events (MACE) and for all-cause mortality. Compared to placebo, canakinumab significantly reduced IL-6 levels in a dose-dependent manner yielding placebo-subtracted median percent reductions in IL-6 at 3 months of 24.8%, 36.3%, and 43.2% for the 50, 150, and 300 mg doses, respectively (all P-values <0.001). By contrast, no dose of canakinumab significantly altered IL-18 levels measured at 3 months (all effects <1%, all P-values > 0.05). Yet, despite these differential plasma effects, either baseline and on-treatment levels of IL-18 or IL-6 associated with rates of future CV events. For example, for MACE, each tertile increase in IL-18 measured 3 months after canakinumab initiation associated with a 15% increase in risk [95% confidence interval (CI) 3–29%, P = 0.016], while each tertile increase in IL-6 measured 3 months after canakinumab initiation associated with a 42% increase in risk (95% CI 26–59%, P < 0.0001). Similar effects were observed for MACE-plus, CV death, all-cause mortality, and the for the combination endpoint of all vascular events inclusive of revascularization procedures and hospitalization for congestive heart failure. In baseline as well as on-treatment analyses, risks were highest among those with the highest levels of both IL-18 and IL-6. Conclusion There remains substantial residual inflammatory risk related to both IL-18 and IL-6 after IL-1β inhibition with canakinumab These data support further pharmacologic development of therapies for atherothrombosis that target IL-18 or IL-6 signalling, or that can simultaneously inhibit both IL-1β and IL-18 (such as NLRP3 inflammasome inhibitors). Clinical trial registration ClinicalTrials.gov NCT01327846.

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Implication of the NLRP3 Inflammasome in Bovine Age-Related Sarcopenia

International Journal of Molecular Sciences ◽

10.3390/ijms22073609 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3609

Author(s):

Davide De Biase ◽

Giuseppe Piegari ◽

Francesco Prisco ◽

Ilaria Cimmino ◽

Ilaria d’Aquino ◽

...

Keyword(s):

Skeletal Muscle ◽

Nlrp3 Inflammasome ◽

Interleukin 1Β ◽

Inflammasome Activation ◽

Interleukin 18 ◽

Necrosis Factor Alpha ◽

Age Related ◽

Factor Alpha ◽

Bovine Skeletal Muscle ◽

First Time

Sarcopenia is defined as the age-related loss of skeletal muscle mass, quality, and strength. The pathophysiological mechanisms underlying sarcopenia are still not completely understood. The aim of this work was to evaluate, for the first time, the expression of NLRP3 inflammasome in bovine skeletal muscle in order to investigate the hypothesis that inflammasome activation may trigger and sustain a pro-inflammatory environment leading to sarcopenia. Samples of skeletal muscle were collected from 60 cattle belonging to three age-based groups. Morphologic, immunohistochemical and molecular analysis were performed to assess the presence of age-related pathologic changes and chronic inflammation, the expression of NLRP3 inflammasome and to determine the levels of interleukin-1β, interleukin-18 and tumor necrosis factor alpha in muscle tissue. Our results revealed the presence of morphologic sarcopenia hallmark, chronic lymphocytic inflammation and a type II fibers-selective NLRP3 expression associated to a significant decreased number of immunolabeled-fibers in aged animals. Moreover, we found a statistically significant age-related increase of pro-inflammatory cytokines such as interleukin-1β and interleukin-18 suggesting the activation of NLRP3 inflammasome. Taken together, our data suggest that NLRP3 inflammasome components may be normally expressed in skeletal muscle, but its priming and activation during aging may contribute to enhance a pro-inflammatory environment altering normal muscular anabolism and metabolism.

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NLRP3 Inflammasome Inhibitors in Cardiovascular Diseases

Molecules ◽

10.3390/molecules26040976 ◽

2021 ◽

Vol 26 (4) ◽

pp. 976

Author(s):

Eleonora Mezzaroma ◽

Antonio Abbate ◽

Stefano Toldo

Keyword(s):

Cardiovascular Diseases ◽

Inflammatory Response ◽

Nlrp3 Inflammasome ◽

Tissue Injury ◽

Scientific Evidence ◽

Rapid Induction ◽

Pyrin Domain ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns ◽

Inflammasome Inhibitors

Virtually all types of cardiovascular diseases are associated with pathological activation of the innate immune system. The NACHT, leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein 3 (NLRP3) inflammasome is a protein complex that functions as a platform for rapid induction of the inflammatory response to infection or sterile injury. NLRP3 is an intracellular sensor that is sensitive to danger signals, such as ischemia and extracellular or intracellular alarmins during tissue injury. The NLRP3 inflammasome is regulated by the presence of damage-associated molecular patterns and initiates or amplifies inflammatory response through the production of interleukin-1β (IL-1β) and/or IL-18. NLRP3 activation regulates cell survival through the activity of caspase-1 and gasdermin-D. The development of NLRP3 inflammasome inhibitors has opened the possibility to targeting the deleterious effects of NLRP3. Here, we examine the scientific evidence supporting a role for NLRP3 and the effects of inhibitors in cardiovascular diseases.

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Transcription Factor EB Alleviates Endothelial Cell Inflammation Through NLRP3 Inflammasome-Mediated Cell Pyroptosis in Atherosclerosis

10.21203/rs.3.rs-132711/v1 ◽

2020 ◽

Author(s):

Fengxia Guo ◽

Bing Hu ◽

Yanhua Sha ◽

Kangning Zhu ◽

Gang Li

Keyword(s):

Transcription Factor ◽

Endothelial Cell ◽

Inflammatory Response ◽

Nlrp3 Inflammasome ◽

Receptor Protein ◽

Enzyme Linked Immunosorbent Assay ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation ◽

Transcription Factor Eb ◽

Amp Activated Protein Kinase

Abstract BackgroundIncreasing evidence suggests that transcription factor EB (TFEB) inhibits inflammation in endothelial cell (ECs) and reduces development of atherosclerosis. However, little is known about the mechanism of action of TFEB on inflammation in atherosclerosis (AS).MethodsThe levels of TFEB, NLRP3, VCAM-1, ICAM-1, E-selectin, MCP-1, cleaved caspase-1, IL-1β and IL-18 in ECs were examined by immunoblotting, quantitative real time-polymerase chain reaction (qRT-PCR) , Enzyme-linked immunosorbent assay. The LDH activity were examined by LDH assay. TUNEL-positive cell were examined by TUNEL assay. The relationship between TFEB and NLRP3 were examined by immunofluorescence and coimmunoprecipitation. The effects of TFEB on atherosclerotic lesions by hematoxylin and eosin, TUNEL and collagen staining in the aortic valve of ApoE-/- mice fed a high fat diet (HFD).ResultsHere, we report that H2O2-induced cell pyroptosis and inflammatory response were mainly due to nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation. The nuclear protein TFEB was significantly increased by H2O2, and knockdown of TFEB aggravated cell pyroptosis and inflammatory response. TFEB directly bound to NLRP3 and blocked NLRP3-mediated cell pyroptosis and inflammatory response. The effect of H2O2 on TFEB might be associated with AMP-activated protein kinase/mechanistic target of rapamycin-dependent signaling pathways.ConclusionsOur findings indicated that a novel TFEB–NLRP3 axis was a critical regulator in EC pyroptosis and inflammation, which could be potential therapeutic targets in AS and related cardiovascular diseases.

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