scholarly journals Migraine and neuroinflammation: the inflammasome perspective

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Oguzhan Kursun ◽  
Muge Yemisci ◽  
Arn M. J. M. van den Maagdenberg ◽  
Hulya Karatas

Abstract Background Neuroinflammation has an important role in the pathophysiology of migraine, which is a complex neuro-glio-vascular disorder. The main aim of this review is to highlight findings of cortical spreading depolarization (CSD)-induced neuroinflammatory signaling in brain parenchyma from the inflammasome perspective. In addition, we discuss the limited data of the contribution of inflammasomes to other aspects of migraine pathophysiology, foremost the activation of the trigeminovascular system and thereby the generation of migraine pain. Main body Inflammasomes are signaling multiprotein complexes and key components of the innate immune system. Their activation causes the production of inflammatory cytokines that can stimulate trigeminal neurons and are thus relevant to the generation of migraine pain. The contribution of inflammasome activation to pain signaling has attracted considerable attention in recent years. Nucleotide-binding domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) is the best characterized inflammasome and there is emerging evidence of its role in a variety of inflammatory pain conditions, including migraine. In this review, we discuss, from an inflammasome point of view, cortical spreading depolarization (CSD)-induced neuroinflammatory signaling in brain parenchyma, the connection with genetic factors that make the brain vulnerable to CSD, and the relation of the inflammasome with diseases that are co-morbid with migraine, including stroke, epilepsy, and the possible links with COVID-19 infection. Conclusion Neuroinflammatory pathways, specifically those involving inflammasome proteins, seem promising candidates as treatment targets, and perhaps even biomarkers, in migraine.

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1652
Author(s):  
Chinmaya Panda ◽  
Clara Voelz ◽  
Pardes Habib ◽  
Christian Mevissen ◽  
Thomas Pufe ◽  
...  

Intra-neuronal misfolding of monomeric tau protein to toxic β-sheet rich neurofibrillary tangles is a hallmark of Alzheimer’s disease (AD). Tau pathology correlates not only with progressive dementia but also with microglia-mediated inflammation in AD. Amyloid-beta (Aβ), another pathogenic peptide involved in AD, has been shown to activate NLRP3 inflammasome (NOD-like receptor family, pyrin domain containing 3), triggering the secretion of proinflammatory interleukin-1β (IL1β) and interleukin-18 (IL18). However, the effect of tau protein on microglia concerning inflammasome activation, microglial polarization, and autophagy is poorly understood. In this study, human microglial cells (HMC3) were stimulated with the unaggregated and aggregated forms of the tau-derived PHF6 peptide (VQIVYK). Modulation of NLRP3 inflammasome was examined by qRT-PCR, immunocytochemistry, and Western blot. We demonstrate that fibrillar aggregates of VQIVYK upregulated the NLRP3 expression at both mRNA and protein levels in a dose- and time-dependent manner, leading to increased expression of IL1β and IL18 in HMC3 cells. Aggregated PHF6-peptide also activated other related inflammation and microglial polarization markers. Furthermore, we also report a time-dependent effect of the aggregated PHF6 on BECN1 (Beclin-1) expression and autophagy. Overall, the PHF6 model system-based study may help to better understand the complex interconnections between Alzheimer’s PHF6 peptide aggregation and microglial inflammation, polarization, and autophagy.


2021 ◽  
Author(s):  
Giuseppe Bombaci ◽  
Mayuresh A Sarangdhar ◽  
Nicola Andina ◽  
Aubry Tardivel ◽  
Eric Chi-Wang Yu ◽  
...  

Inflammasomes are cytosolic innate immune sensors that, upon activation, induce caspase-1 mediated inflammation. Although inflammation is protective, uncontrolled excessive inflammation can cause inflammatory diseases and is also detrimental in COVID-19 infection. However, the underlying mechanisms that control inflammasome activation are incompletely understood. Here we report that the leucine rich repeat (LRR) protein Ribonuclease inhibitor (RNH1), which shares homology with LRRs of NOD-like receptor family pyrin domain (PYD)-containing (NLRP) proteins, attenuates inflammasome activation. Mechanistically, RNH1 decreased pro-IL1b expression and induced proteasome-mediated caspase-1 degradation. Corroborating this, mouse models of monosodium urate (MSU)-induced peritonitis and LPS-induced endotoxemia, which are dependent on caspase-1, respectively showed increased neutrophil infiltration and lethality in Rnh1-/- mice compared to WT mice. Further, RNH1 protein levels were negatively correlated with inflammation and disease severity in hospitalized COVID-19 patients. We propose that RNH1 is a new inflammasome regulator with relevance to COVID-19 severity.


2020 ◽  
pp. 116-121
Author(s):  
Kseniia Ivanova

Problem setting. One of the subsystems of the National Innovative System is the field of technology transfer. Considering the NIS from the point of view of the interests pursued by its participants (subjects), the mechanism introduced by the legislator, providing legal regulation of certain social relations, directly depends on what interests they pursue. Analysis of recent researches and publications. The following scientists drew attention to the problems of regulation of relations in the field of technology transfer: O. M. Davydiuk, Yu. M. Kapitsa, D. S. Makhnovsky, V. S. Milash, O. P. Orlyuk, B. M. Paduchak, O. E. Simson. However, further study of these relations remains relevant especially in view of the constant updating of current legislation. Target of research is to analyze the mechanisms for satisfying the interests of participants (subjects) of technology transfer, which are introduced in the current legislation and are proposed for the future. Article’s main body. Considering the national innovative system from the point of view of the interests pursued by its participants (subjects), we can distinguish the interests of the author of the technology, recipient, technology donor and the state, whose interests determine the overall vector of the transfer process. The primary subject in technology transfer is the author of the technology – an individual who can act as a direct participant (subject) of technology transfer and be its donor, who independently decides the legal fate of the technology and / or its components. However, the author of the technology may not be a donor when it comes to the relationship between him and his employer as a performer of scientific research and development work for the budget. In this case, although the technology is created by the direct work of the author-employee, property rights to the technology are assigned to the enterprise, research institution, organization or institution of higher education as the executor of these works (organization-developer), and the author is entitled to royalties. Thus, a compromise is reached between the parties and provides the necessary balance of interests of the employer and the author. In the transfer of technology, which occurs through the conclusion of the contract, the interests of the parties to the contract are mutually conditioned. These entities, realizing their property interests, act in contractual relations on the principle of dispositiveness, ie equality of the parties, and the state does not interfere in these relations. And only when the sphere of interests of the subjects of transfer affects the interests of the state, the relationship is complicated by the establishment of additional requirements and / or procedures (in particular, the export of technologies created or purchased from the budget). The interest of the state in this case is due to the purpose of preserving national and technological security, control over the misuse of budget funds during the financing of R & D, solving other strategic tasks. The protective mechanism of legal support of the state’s interests introduced in the Law is implemented through the establishment of requirements for the use of technology and / or their components, created or purchased for budget funds, mainly on the territory of Ukraine; conducting state expertise for technologies and / or their components, which are purchased for budget funds (including through their import). Meanwhile, the world practice is aware of other means aimed at protecting the interests of the state, such as control over the re-export of technology in order to eliminate the possibility of further transfer of technology from its donor to others. Conclusions and prospects for the development. The field of technology transfer is characterized by a combination of imperative and dispositive methods of legal regulation. When concluding a technology transfer agreement, the parties agree on its terms, based on their own interests and the requirements for certain types of agreements. However, lawyers note: the wider the range of interests (individual, group), which are directly or indirectly affected by the contract, the more important should be the degree of legal regulation. Therefore, when it comes to the interests of the state, the legislator should not neglect the ability to imperatively determine the requirements to be met by the parties in technology transfer and which provide for the implementation of additional incentives for the introduction of domestic technologies into circulation, their practical application in production.


2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Mathias S. Dick ◽  
Lorenzo Sborgi ◽  
Sebastian Rühl ◽  
Sebastian Hiller ◽  
Petr Broz

Abstract A hallmark of inflammasome activation is the ASC speck, a micrometre-sized structure formed by the inflammasome adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD), which consists of a pyrin domain (PYD) and a caspase recruitment domain (CARD). Here we show that assembly of the ASC speck involves oligomerization of ASCPYD into filaments and cross-linking of these filaments by ASCCARD. ASC mutants with a non-functional CARD only assemble filaments but not specks, and moreover disrupt endogenous specks in primary macrophages. Systematic site-directed mutagenesis of ASCPYD is used to identify oligomerization-deficient ASC mutants and demonstrate that ASC speck formation is required for efficient processing of IL-1β, but dispensable for gasdermin-D cleavage and pyroptosis induction. Our results suggest that the oligomerization of ASC creates a multitude of potential caspase-1 activation sites, thus serving as a signal amplification mechanism for inflammasome-mediated cytokine production.


2017 ◽  
Vol 216 (9) ◽  
pp. 2891-2909 ◽  
Author(s):  
Paola Kuri ◽  
Nicole L. Schieber ◽  
Thomas Thumberger ◽  
Joachim Wittbrodt ◽  
Yannick Schwab ◽  
...  

Activated danger or pathogen sensors trigger assembly of the inflammasome adaptor ASC into specks, large signaling platforms considered hallmarks of inflammasome activation. Because a lack of in vivo tools has prevented the study of endogenous ASC dynamics, we generated a live ASC reporter through CRISPR/Cas9 tagging of the endogenous gene in zebrafish. We see strong ASC expression in the skin and other epithelia that act as barriers to insult. A toxic stimulus triggered speck formation and rapid pyroptosis in keratinocytes in vivo. Macrophages engulfed and digested that speck-containing, pyroptotic debris. A three-dimensional, ultrastructural reconstruction, based on correlative light and electron microscopy of the in vivo assembled specks revealed a compact network of highly intercrossed filaments, whereas pyrin domain (PYD) or caspase activation and recruitment domain alone formed filamentous aggregates. The effector caspase is recruited through PYD, whose overexpression induced pyroptosis but only after substantial delay. Therefore, formation of a single, compact speck and rapid cell-death induction in vivo requires a full-length ASC.


2015 ◽  
Vol 112 (10) ◽  
pp. 3056-3061 ◽  
Author(s):  
Jayendra Kumar Krishnaswamy ◽  
Arpita Singh ◽  
Uthaman Gowthaman ◽  
Renee Wu ◽  
Pavane Gorrepati ◽  
...  

Dendritic cells (DCs) are the primary leukocytes responsible for priming T cells. To find and activate naïve T cells, DCs must migrate to lymph nodes, yet the cellular programs responsible for this key step remain unclear. DC migration to lymph nodes and the subsequent T-cell response are disrupted in a mouse we recently described lacking the NOD-like receptor NLRP10 (NLR family, pyrin domain containing 10); however, the mechanism by which this pattern recognition receptor governs DC migration remained unknown. Using a proteomic approach, we discovered that DCs from Nlrp10 knockout mice lack the guanine nucleotide exchange factor DOCK8 (dedicator of cytokinesis 8), which regulates cytoskeleton dynamics in multiple leukocyte populations; in humans, loss-of-function mutations in Dock8 result in severe immunodeficiency. Surprisingly, Nlrp10 knockout mice crossed to other backgrounds had normal DOCK8 expression. This suggested that the original Nlrp10 knockout strain harbored an unexpected mutation in Dock8, which was confirmed using whole-exome sequencing. Consistent with our original report, NLRP3 inflammasome activation remained unaltered in NLRP10-deficient DCs even after restoring DOCK8 function; however, these DCs recovered the ability to migrate. Isolated loss of DOCK8 via targeted deletion confirmed its absolute requirement for DC migration. Because mutations in Dock genes have been discovered in other mouse lines, we analyzed the diversity of Dock8 across different murine strains and found that C3H/HeJ mice also harbor a Dock8 mutation that partially impairs DC migration. We conclude that DOCK8 is an important regulator of DC migration during an immune response and is prone to mutations that disrupt its crucial function.


2018 ◽  
Vol 315 (6) ◽  
pp. G909-G920 ◽  
Author(s):  
Lanju Wang ◽  
Yaohui Wang ◽  
Zhenfeng Wang ◽  
Yu Qi ◽  
Beibei Zong ◽  
...  

Growth differentiation factor 11 (GDF11) has an anti-inflammatory effect in the mouse model of atherosclerosis and Alzheimer's disease, but how GDF11 regulates intestinal inflammation during ulcerative colitis (UC) is poorly defined. The Nod-like receptor family pyrin domain-1 containing 3 (NLRP3) inflammasome is closely associated with intestinal inflammation because of its ability to increase IL-1β secretion. Our aim is to determine whether GDF11 has an effect on attenuating experimental colitis in mice. In this study, using a dextran sodium sulfate (DSS)-induced acute colitis mouse model, we reported that GDF11 treatment attenuated loss of body weight, the severity of the disease activity index, shortening of the colon, and histological changes in the colon. GDF11 remarkably suppressed IL-1β secretion and NLRP3 inflammasome activation in colon samples and RAW 264.7 cells, such as the levels of NLRP3 and activated caspase-1. Furthermore, we found that GDF11 inhibited NLRP3 inflammasome activation by downregulating the Toll-like receptor 4/NF-κB p65 pathway and reactive oxygen species production via the typical Smad2/3 pathway. Thus, our research shows that GDF11 alleviates DSS-induced colitis by inhibiting NLRP3 inflammasome activation, providing some basis for its potential use in the treatment of UC. NEW & NOTEWORTHY Here, we identify a new role for growth differentiation factor 11 (GDF11), which ameliorates dextran sodium sulfate-induced acute colitis. Meanwhile, we discover a new phenomenon of GDF11 inhibiting IL-1β secretion and Nod-like receptor family pyrin domain-1 containing 3 (NLRP3) inflammasome activation. These findings reveal that GDF11 is a new potential candidate for the treatment of ulcerative colitis patients with a hyperactive NLRP3 inflammasome.


Hepatology ◽  
2019 ◽  
Vol 69 (2) ◽  
pp. 845-859 ◽  
Author(s):  
Maria Eugenia Inzaugarat ◽  
Casey D. Johnson ◽  
Theresa Maria Holtmann ◽  
Matthew D. McGeough ◽  
Christian Trautwein ◽  
...  

Author(s):  
Marcelle de Carvalho Ribeiro ◽  
Gyongyi Szabo

The involvement of inflammasomes in the proinflammatory response observed in chronic liver diseases, such as alcohol-associated liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD), is widely recognized. Although there are different types of inflammasomes, most studies to date have given attention to NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3) in the pathogenesis of ALD, NAFLD/nonalcoholic steatohepatitis, and fibrosis. Canonical inflammasomes are intracellular multiprotein complexes that are assembled after the sensing of danger signals and activate caspase-1, which matures interleukin (IL)-1β, IL-18, and IL-37 and also induces a form of cell death called pyroptosis. Noncanonical inflammasomes activate caspase-11 to induce pyroptosis. We discuss the different types of inflammasomes involved in liver diseases with a focus on ( a) signals and mechanisms of inflammasome activation, ( b) the role of different types of inflammasomes and their products in the pathogenesis of liver diseases, and ( c) potential therapeutic strategies targeting components of the inflammasomes or cytokines produced upon inflammasome activation. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.


2020 ◽  
pp. 71-74
Author(s):  
Yulia Ryzhkova

Problem setting. Many decades have passed since the Pact was signed, and the essential nature of the it continues to spark debate among historians and scholars. The main criterion that continues debates is the fact that the signing of the act resulted in a change of the entire European continent and a change in the geopolitical balance. Therefore, the relevance of the topic is that today there is no clear political and moral assessment of the pact on the basis of which a rational international significance of the document could be established. Target of research. The purposes of this study are to establish the legal characteristics and nature of the Molotov – Ribbentrop Pact; to analyze the consequences of which the document has been signed; to distinguish the positive and negative sides of the act in combination with the proposal of its international significance. Analysis of resent researches and publications. The following scientists were engaged in research of the specified question: M. Shvagulak, S. Pron, I. Khalupa, Nicolas Burns and Andreas Ortega. Article’s main body. This publication discusses the document – the Molotov-Ribbentrop Pact, which has had a significant impact on both political and social development and the future potential of dozens of countries across the European continent. The Pact still defines many geopolitical realities in modern Europe. Discussions about the historic role of the non-aggression treaty and secret protocols are still relevant. The article deals with the legal characterization and essence of an international act of political and legal nature. The consequences of the signature of the “fateful sentence” are analyzed, as well as the positive and negative sides of this document, in combination with the establishment of its international significance, are highlighted and presented in detail. Conclusions and prospects for the development. Thus, as can be seen from all the work, the Molotov – Ribbentrop Pact has a rather contradictory character, both in relation to the countries it has in some way concerned and to history in general. So, on the one hand, this treaty was really beneficial and needed by the countries that signed it, namely Germany and the Soviet Union. However, the benefits in each of these countries were different. Discussions are still ongoing about the legal force of the treaty, as well as its international legal assessment. But from the point of view of international law, the Pact should be regarded as a huge violation that has influenced the development of new rules and principles in modern society. That is why the author believes that it is the Molotov – Ribbentrop Pact that became the signature of both states in the face of the forthcoming explosion of the largest Second world war.


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