Multiple sclerosis

Nature Reviews Disease Primers, Journal Year: 2018, Volume and Issue: 4(1)

Published: Nov. 8, 2018

Language: Английский

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Inflammasomes in neuroinflammatory and neurodegenerative diseases

EMBO Molecular Medicine, Journal Year: 2019, Volume and Issue: 11(6)

Published: April 23, 2019

Review23 April 2019Open Access Inflammasomes in neuroinflammatory and neurodegenerative diseases Sofie Voet VIB Center for Inflammation Research, Ghent, Belgium Department of Biomedical Molecular Biology, Ghent University, Search more papers by this author Sahana Srinivasan Mohamed Lamkanfi Corresponding Author [email protected] orcid.org/0000-0002-4898-7663 Internal Medicine, Janssen Immunosciences, World without Disease Accelerator, Pharmaceutical Companies Johnson & Johnson, Beerse, Geert van Loo orcid.org/0000-0002-8427-4775 Information Voet1,2, Srinivasan1,2, *,3,4 *,1,2 1VIB 2Department 3Department 4Janssen *Corresponding author. Tel: +32 14 605 343; E-mail: 93313761; Fax: 92217673; EMBO Mol Med (2019)11:e10248https://doi.org/10.15252/emmm.201810248 See the Glossary abbreviations used article. PDFDownload PDF article text main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures Info Abstract Neuroinflammation neurodegeneration often result from aberrant deposition aggregated host proteins, including amyloid-β, α-synuclein, prions, that can activate inflammasomes. function as intracellular sensors both microbial pathogens foreign well host-derived danger signals. Upon activation, they induce an innate immune response secreting inflammatory cytokines interleukin (IL)-1β IL-18, additionally inducing pyroptosis, a lytic cell death mode releases additional mediators. Microglia are prominent cells brain inflammasome activation. However, CNS-resident types astrocytes neurons, infiltrating myeloid periphery, express In review, we will discuss current understanding role inflammasomes common degenerative highlight inflammasome-targeted strategies may potentially treat these diseases. Blood–brain barrier (BBB) physiological between blood CNS parenchyma. The BBB is formed endothelial joined complex tight junctions coated basement membrane astrocytic end-feet, known glia limitans. Caspases family cysteine-dependent aspartate specific proteases play central inflammation programmed death. Cerebrospinal fluid (CSF) contained ventricles cranial spinal subarachnoid spaces. It provides mean transporting different molecules, cytokines, neurotransmitters, hormones, but also resides cells. macrophages non-parenchymal located meninges, choroid plexus, perivascular Creutzfeldt–Jakob disease fatal prion be sporadic, hereditary, or acquired. acquired form caused exposure misfolded scrapie PrP protein. Cuprizone-induced demyelination experimental model study local corpus callosum, which induced administration copper chelator cuprizone (bis(cyclohexanone)oxaldihydrazone) food mice during 5 weeks. Dopaminergic neurons dopamine-producing essential controlling key functions brain, voluntary movement, reward processing, mood, working memory. Encephalomyelitis general term describe cord. Autoimmune encephalomyelitis abnormal self-antigen. Experimental autoimmune (EAE) rodent MS. EAE actively peripheral immunization with myelin-specific proteins peptides combination adjuvant, passively transfer encephalitogenic T Familial Mediterranean Fever most monogenic autoinflammatory characterized periodic fevers childhood onset, frequently associated serositis joint pain. predominantly affects populations. Grand-mal seizures tonic-clonic seizures: loss consciousness violent muscle contractions. This seizure comes two phases: tonic phase followed clonic phase. brief features stiffening, while muscles go into rhythmic Induced pluripotent stem (iPSCs) generated genetic reprogramming adult somatic advantage over other not derived human embryo. Ischemic infarct interruption flow due occlusion cerebral vessel. Middle artery stroke involves permanent transient middle artery. one three arteries supply cerebrum. "filament model", suture filament (transiently) introduced internal carotid forwarded until tip occludes Neonatal-onset multisystem (NOMID) chronic infantile neurologic cutaneous articular (CINCA): severe cryopyrin-associated syndrome (CAPS). NOMID neonatal-onset skin lesions, aseptic meningitis, recurrent fever along symptoms. Sepsis life-threatening systemic (SIRS) body's infection. Spatial memory important cognitive allows us recall three-dimensional objects places. Steatohepatitis type fatty liver accumulation lipids infiltration hepatic Striata dopamine substantia nigra pars compacta project caudate putamen basal ganglia, together referred striatum. Substantia structure brainstem contains neurons. Introduction system rapid coordinated cellular defense aims eliminate threat posed sterile infectious insults. Recognition pathogenic agents mediated pattern recognition receptors (PRRs) sense pathogen-associated molecular patterns (PAMPs) host- environment-derived danger-associated (DAMPs). nervous (CNS), PRRs primarily expressed microglia, astrocytes, macrophages, oligodendrocytes, repertoire (Lampron et al, 2013; Walsh 2014). either membrane-bound, case Toll-like (TLRs), signals extracellular environment endosome, intracellular, nucleotide-binding domain leucine-rich repeat-containing (NLRs) AIM2-like (ALRs). An subgroup cytosolic includes members NLR ALR families tripartite motif (TRIM) member pyrin critically contributes assembling so-called "inflammasomes". General concepts biology multiprotein complexes upon assembly pro-inflammatory caspase-1 (see Glossary) responsible maturation secretion IL-1β pyroptosis (Lamkanfi Dixit, 2014; Broz 2016). Briefly, inflammasome-inducing stimuli trigger oligomerization PRR recruitment pre-existing procaspase-1 zymogens complex, leading their proximity-induced autoactivation generate active caspase-1. Consequently, cleave biologically inactive pro-peptides pro-IL-1β pro-IL-18 mature then secreted cell. Next its pro-IL-18, death, early plasma rupture, thereby releasing soluble fraction fuels 2012, Central process executioner protein gasdermin D (GSDMD)—a substrate murine caspase-11, caspase-1, caspase-4, caspase-5—the amino-terminal cleavage oligomerizes perforates swelling osmotic lysis (Shi 2017) (Fig 1). Figure 1. Inflammasome activation signalingInflammasomes assemble stimulus-specific manner. Different DAMPs PAMPs able NLRP3, NLRP1b responds Bacillus anthracis lethal toxin, NLRC4 recognizes bacterial flagellin and/or III pathogens, AIM2 specifically activated dsDNA, inactivation RhoA toxins effector proteins. Activation NLRP3 two-step mechanism. priming signal detected membrane-bound PRRs, TLRs C-type lectin (CLRs) induces NF-κB-dependent transcription precursor protein, controls post-translational modifications license second necessary formation, depending on subsequent procaspase-1. Active cleaves forms IL-18 get secreted. addition, D, N-terminal fragment translocates pore formation pyroptotic contrast do need initial cytokine release. Download figure PowerPoint One way classify based receptor initiates signaling 2012). core components consist NLR, ALR, receptors, adaptor apoptosis-associated speck-like containing caspase (ASC) ASC composed (PYD) (CARD) links PYD CARD 2). Some inflammasomes, such NLRP1b, require directly recruit through respective CARDs, although under wild-type conditions does contribute optimal efficient (Broz 2010; Guey Van Opdenbosch Assembly requires detection signals: Murine Nlrp1b toxin (LeTx) (Boyden Dietrich, 2006); detects systems (T3SS) (Franchi 2006; Miao 2006, 2010); physically binds double-stranded DNA (dsDNA) (Hornung 2009); indirectly covalently inactivate small GTPase (Xu widely studied inflammasome, broad spectrum activating suite bacterial, fungal, viral PAMPs, ATP uric acid crystals, crystalline substances asbestos, silica, amyloid-β fibrils unique it process. A first signal, results transcriptional upregulation pro-IL-1β, highlighted mapped ubiquitin phosphorylation sites (Yang 2017). "activation" Besides canonical signaling, non-canonical pathway caspase-11 (or orthologs caspase-4 caspase-5) LPS, induction GSDMD release high mobility group box 1 (HMGB1) IL-1α Shi Apart NAIP/NLRC4 complexes, secondary messengers physical ligands bind await discovery. 2. Domain inflammasomesA subset NLRs ALRs have (NACHT/NBD), repeat (LRR) motifs, typically center carboxy terminus respectively. NACHT usually flanked domain, PYD, domains further sub-classification These allow complex. gene consists 22 34 members, many always clear 2012; addition NLR-containing DNA-binding HIN200 2009). Pyrin, TRIM20, B-boxes, coiled-coil whereas has C-terminal B30.2 domain. critical domains, latter being homotypic interaction PYD-containing sensor (NLRP3, AIM2). Procaspase-1 interactions direct indirect (via ASC) recruitment, resulting macromolecular aggregate, speck CNS, cognate initiate cascades neuronal injury (Allan 2005; Alboni 2010). Hence, increased levels observed infection, injury, (Heneka 2014, 2018). been shown participate processes cognition, learning, (Tsai, Pyroptosis inflammasome-driven pathology mediators DAMPs. Apoptosis necroptosis modes promote neuroinflammation degeneration several pathologies, multiple sclerosis, amyotrophic lateral Parkinson's disease, Alzheimer's (Zhang 2017; Yuan 2019). Although mainly attributed expression reported (Kaushal 2015), (Freeman 2017), (Kawana 2013), oligodendrocytes (Mckenzie 2018), (Gong 2018) 3). microglia still fragmentary vitro studies primary microglial lines, vivo transgenic knockout lack throughout body. More appropriate research tools CNS-specific targeting needed investigate relative contribution overall pathology. Furthermore, evidence patients relies higher transcript components. NF-κB responsive genes largely indicative ongoing rather than support engagement. We here review knowledge relevance pathologies 3 Table 1) emerging treatment diseases, Zika, HIV, West Nile virus, infections meningitis (Walsh Mamik Power, Heneka outside scope review. 3. diseaseInflammasomes acute (traumatic stroke), autoimmune-mediated (multiple sclerosis), (Alzheimer's disease). demonstrated types, CNS-infiltrating cells, macrophages. focused importance disorders. Overall, caspase-1-mediated cytokines. High considered crucial establishment environment, dysfunction eventually neurodegeneration. Overview described models Description Multiple sclerosis Cuprizone Administration callosum Stroke Permanent MCAO obtained using intraluminal Transient Intraluminal utilizes inserted interrupt duration afterward removed. Embolic uses autologous clot injected MCA occlude vessel Intracerebral hemorrhage (ICH) condition provoked injection arterial ganglia TBI SCI Controlled cortical impact (CCI) mechanical traumatic injury. Following craniotomy, CCI device mechanically transfers energy onto dura mater damaging cortex, sometimes subcortical structures Impact acceleration exposed skull covered steel disk weight dropped Contusion cord force applied electromagnetic weight-drop displace damage Alzheimer APP/PS1 Mouse expressing APP695 Swedish double mutation (K670N/M671L) mutant presenilin (PS1-dE9) 3xTgAD (K670N/M671L), PS1 M146V mutation, Tau P301L Tg2567 at β-secretase site 5xFAD APP PSEN1 transgenes total five AD-linked mutations: Florida (I716V), London (V717I) mutations APP, M146L L286V Amyotrophic TgSOD1-G93A G93A SOD1 hSOD1 G37R G85R Parkinson A53T alpha-synuclein. LPS-induced PD Injection LPS left 6-hydroxydopamine-induced 6-hydroxydopamine medial forebrain bundle MPTP-induced Intraperitoneal MPTP times 2-h intervals Prion Scrapie-infected homogenate strain 139A-infected intracerebral RML6 (passage 6 Rocky Mountain Laboratory mouse-adapted prions) Tg(CJD) (D177N/V128) Huntington R6/2 Transgenic exon huntingtin expanded CAG/polyglutamine (MS) CNS. MS compromised blood–brain leads periphery astrocyte inflammation, demyelination, (Baecher-Allan (Ransohoff, 2012), were (Sutton Gris Lévesque Most involvement shaped lymphocytes enter Caspase-1, upregulated mononuclear (PBMCs) cerebrospinal patients, inflammasome-activating (Inoue Shinohara, Moreover, was elevated demyelinating lesions (Voet recently proposed candidate biomarkers onset (Keane EAE-associated T-cell trafficking supported analysis (Furlan 1999; Inoue 2012a). pharmacological inhibitor MCC950/CRID3 suppress production attenuate severity (Coll 2015). Similarly, blockade protease activity Z-Val-Ala-DL-Asp-fluoromethylketone prodrug VX-765 reduced symptoms Mckenzie Interestingly, IFNβ, line MS, only effective inflammasome-dependent subtype, NLRP3-independent could reversed IFN-β therapy 2012b, provided border-associated anti-inflammatory A20 negatively regulate (Vande Walle 2014), deletion exacerbated hyperactivation resulted CNS-intrinsic another showed caspase-1- GSDMD-mediated myelin-forming cuprizone-induced NLRP3-deficient presented delayed oligodendrocyte loss, (Jha Additional similar observations mice, unlike protection had differential effect remyelination after treatment, demonstrating delay accelerated seen knockouts plays pathological stroke, identified So far, four distinct implicated viz. NLRP1, NLRC4, (Barrington Additionally, (MCAO), mouse (Kang 2000). Expression products IL-1β, postmortem tissue (Fann 2013). Studies inhibitors caspases caspase-1-deficient mice—that later (Kayagaki 2011)—showed (Friedlander 1997; Hara Schielke 1998; Rabuffetti 2000; Ross 2007). agreement, deficient exhibited dramatically ischemic volumes (Boutin 2001), IL-18-deficient did show (Wheeler 2003). deficiency MCC950/CRID3, intracerebroventricular siRNAs all ameliorated clinical outcomes (Ma Yang 2015; Ismael 2018b). Also, NLRC4- AIM2-deficient significantly smaller compared subjected tMCAO, strongly leukocyte (Denes Finally, peri-infarct zone rats revealed AIM2, (Lammerding 2016), consistent potential mu

Language: Английский

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The Role of Astrocytes in CNS Inflammation

Trends in Immunology, Journal Year: 2020, Volume and Issue: 41(9), P. 805 - 819

Published: Aug. 13, 2020

Language: Английский

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Microglia in Central Nervous System Inflammation and Multiple Sclerosis Pathology

Trends in Molecular Medicine, Journal Year: 2018, Volume and Issue: 25(2), P. 112 - 123

Published: Dec. 18, 2018

Language: Английский

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MAFG-driven astrocytes promote CNS inflammation

Nature, Journal Year: 2020, Volume and Issue: 578(7796), P. 593 - 599

Published: Feb. 12, 2020

Language: Английский

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Function and therapeutic value of astrocytes in neurological diseases

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 21(5), P. 339 - 358

Published: Feb. 16, 2022

Language: Английский

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An Activity-Guided Map of Electrophile-Cysteine Interactions in Primary Human T Cells

Cell, Journal Year: 2020, Volume and Issue: 182(4), P. 1009 - 1026.e29

Published: July 29, 2020

Language: Английский

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Exosomes derived from mesenchymal stem cells attenuate inflammation and demyelination of the central nervous system in EAE rats by regulating the polarization of microglia

International Immunopharmacology, Journal Year: 2018, Volume and Issue: 67, P. 268 - 280

Published: Dec. 16, 2018

Language: Английский

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Gut Microbiome in Progressive Multiple Sclerosis

Annals of Neurology, Journal Year: 2021, Volume and Issue: 89(6), P. 1195 - 1211

Published: April 20, 2021

Objective This study was undertaken to investigate the gut microbiome in progressive multiple sclerosis (MS) and how it relates clinical disease. Methods We sequenced microbiota from healthy controls relapsing–remitting MS (RRMS) patients correlated levels of bacteria with features disease, including Expanded Disability Status Scale (EDSS), quality life, brain magnetic resonance imaging lesions/atrophy. colonized mice MS‐derived Akkermansia induced experimental autoimmune encephalomyelitis (EAE). Results Microbiota β‐diversity differed between but did not differ RRMS or based on disease‐modifying therapies. Disease status had greatest effect β‐diversity, followed by body mass index, race, sex. In both RRMS, we found increased Clostridium bolteae , Ruthenibacterium lactatiformans decreased Blautia wexlerae Dorea formicigenerans Erysipelotrichaceae CCMM . Unique MS, elevated Enterobacteriaceae g24 FCEY Agathobaculum Several species were associated higher EDSS fatigue scores. Contrary view that has a detrimental role, linked lower disability, suggesting beneficial role. Consistent this, isolated ameliorated EAE, which reduction RORγt+ IL‐17–producing γδ T cells. Interpretation Whereas some alterations are shared relapsing identified unique measures Furthermore, may be compensatory response microbiome. ANN NEUROL 2021;89:1195–1211

Language: Английский

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Environmental Control of Astrocyte Pathogenic Activities in CNS Inflammation

Cell, Journal Year: 2019, Volume and Issue: 176(3), P. 581 - 596.e18

Published: Jan. 1, 2019

Language: Английский

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