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Cited by 110Inflammasome and immune disordersMultiple Sclerosis Research StudiesNeuroinflammation and Neurodegeneration Mechanisms

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Role of inflammasomes in multiple sclerosis and their potential as therapeutic targets

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Govindarajan, Vaidya, de Rivero Vaccari, Juan Pablo, Keane, Robert W.·2020·Journal of Neuroinflammation
DOI 10.1186/s12974-020-01944-9PMC PMC7469327
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Abstract

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS), and it remains the most common immune-mediated disorder affecting the CNS. While the cause of MS is unclear, the underlying pathomechanisms are thought to be either destruction by autoimmune T cells or dysfunction of myelin-producing cells. Recent advances have indicated that inflammasomes contribute the etiology of MS. Inflammasomes are multiprotein complexes of the innate immune response involved in the processing of caspase-1, the activation of pro-inflammatory cytokines interleukin (IL)-1β and IL-18 as well as the cell death-mediated mechanism of pyroptosis and the activation of the adaptive immune response. Here we review the literature to date on the role of different inflammasome signaling pathways in the pathogenesis of MS and how these pathways may be targeted to reduce deleterious inflammatory processes and improve outcomes in this patient population.

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Figures

Fig. 1 Induction and interactions of γδ T cell and Th17 cell signaling pathways in MS and EAE. In the induction phase, pathogen-associated molecular patterns (PAMP) from commensal bacteria and danger-associated molecular patterns (DAMP) from dead/dying cells bind to pattern recognition receptors (PRR) on monocytes and dendritic cells (DC). Activated DC and monocytes secrete interleukin (IL)-β, IL-23, and IL-6. IL-β and IL-23 activate γδ T cells leading to IL-17, IL-21, and granulocyte-macrophage colony stimulating factor (GM-CSF) production. Activated DC present antigenic peptide by MHC class II molecules to T cell receptors (TCR) on Tnaive (CD4) T cells. Antigenic peptide presentation along with co-stimulatory signals from DC (IL1-β, IL-6 and IL-23) activates Th17 cells that respond and secrete IL-17, GM-CSF, and IL-21. These cytokines are also released from activated γδ T cells and jointly combine to initiate pro-inflammatory feedback loops that augment the production of IL-1β, IL-6, and IL-23 by antigen presenting cells (APC), leading to enhanced Th17 responses and continued γδ T cell activation of the effector phase. IL-17 and IL-21 act in an autocrine manner to enhance IL-17 production by Th17 T cells in the development of EAE. Lastly, activated γδ T cells suppress T regulatory (Treg) responses, promoting the pro-inflammatory profile by effector T cells. Adapted from McGinley et al. [1]
Fig. 1 Induction and interactions of γδ T cell and Th17 cell signaling pathways in MS and EAE. In the induction phase, pathogen-associated molecular patterns (PAMP) from commensal bacteria and danger-associated molecular patterns (DAMP) from dead/dying cells bind to pattern recognition receptors (PRR) on monocytes and dendritic cells (DC). Activated DC and monocytes secrete interleukin (IL)-β, IL-23, and IL-6. IL-β and IL-23 activate γδ T cells leading to IL-17, IL-21, and granulocyte-macrophage colony stimulating factor (GM-CSF) production. Activated DC present antigenic peptide by MHC class II molecules to T cell receptors (TCR) on Tnaive (CD4) T cells. Antigenic peptide presentation along with co-stimulatory signals from DC (IL1-β, IL-6 and IL-23) activates Th17 cells that respond and secrete IL-17, GM-CSF, and IL-21. These cytokines are also released from activated γδ T cells and jointly combine to initiate pro-inflammatory feedback loops that augment the production of IL-1β, IL-6, and IL-23 by antigen presenting cells (APC), leading to enhanced Th17 responses and continued γδ T cell activation of the effector phase. IL-17 and IL-21 act in an autocrine manner to enhance IL-17 production by Th17 T cells in the development of EAE. Lastly, activated γδ T cells suppress T regulatory (Treg) responses, promoting the pro-inflammatory profile by effector T cells. Adapted from McGinley et al. [1]CC BY · PubMed Central
Fig. 2 Key pathological processes within blood and central nervous system (CNS) during EAE and MS. (1) Danger associate molecular patterns (DAMP) and Pathogen-Associated molecular patterns (PAMP) released into the peripheral blood activate inflammatory myeloid and T cells that migrate into the CNS after blood-brain barrier (BBB) breakdown. (2) Infiltrating monocytes and neutrophils release IL-1β that activates γδ T cells to secrete IL-17, IL-21 and blood-brain barrier (TNF), which amplifies Th17 responses. In addition, activation of inflammatory myeloid cells releases granulocyte-macrophage colony stimulating factor (GM-CSF) that amplifies Th17 cell activation (3) IFN-γ and GM-CSF released from Th1 cells, and IL-17, interferon (IFN)-γ and tumor necrosis factor (TNF) released from activated Th17 cells activate microglia. (4) T cell re-activation by presented myelin antigens. (5) Clonal expansion of T effector (Teff) cells. (6) Activation of infiltrating and resident cells results in the release of inflammatory mediators by Th1 and Th17 cells (IL-17, GM-CSF, IFN-γ, TNF) and production of reactive oxygen and nitrogen species, cytotoxic products and proteases that promote the destruction of myelin around axons (7) and oligodendrocytes (8), which are responsible for axonal remyelination, resulting in a toxic inflammatory response that leads to neuronal death and neurological deficits. Adapted from McGinley et al. [1]
Fig. 2 Key pathological processes within blood and central nervous system (CNS) during EAE and MS. (1) Danger associate molecular patterns (DAMP) and Pathogen-Associated molecular patterns (PAMP) released into the peripheral blood activate inflammatory myeloid and T cells that migrate into the CNS after blood-brain barrier (BBB) breakdown. (2) Infiltrating monocytes and neutrophils release IL-1β that activates γδ T cells to secrete IL-17, IL-21 and blood-brain barrier (TNF), which amplifies Th17 responses. In addition, activation of inflammatory myeloid cells releases granulocyte-macrophage colony stimulating factor (GM-CSF) that amplifies Th17 cell activation (3) IFN-γ and GM-CSF released from Th1 cells, and IL-17, interferon (IFN)-γ and tumor necrosis factor (TNF) released from activated Th17 cells activate microglia. (4) T cell re-activation by presented myelin antigens. (5) Clonal expansion of T effector (Teff) cells. (6) Activation of infiltrating and resident cells results in the release of inflammatory mediators by Th1 and Th17 cells (IL-17, GM-CSF, IFN-γ, TNF) and production of reactive oxygen and nitrogen species, cytotoxic products and proteases that promote the destruction of myelin around axons (7) and oligodendrocytes (8), which are responsible for axonal remyelination, resulting in a toxic inflammatory response that leads to neuronal death and neurological deficits. Adapted from McGinley et al. [1]CC BY · PubMed Central
Fig. 3 Mechanism of action of the NLRP3 inflammasome. In the canonical pathway, the priming step involves the recognition of pathogen-associated molecular pattern (PAMP) or a danger-associated molecular pattern (DAMP) by a pattern recognition receptor (PRR) or toll-like receptor (TLR), which recruits the adaptor protein myeloid differentiation primary response 88 (MYD88) into the receptor complex leading to phosphorylation of the inhibitor of nuclear factor-kB (NFκB) IκB through interaction with the p50 and p65 transcription factors. Activation of the NF-κB pathway causes the synthesis of pro-IL-1-β or pro-IL-18. NLRP3 is activated by lysosomal-mediated cathepsin B via lysosome rupture, reactive oxygen species (ROS), oxidized mitochondrial (Mt) DNA, altered Ca2+ concentration via mitochondrial dysfunction, and adenosine triphosphate (ATP) efflux and potassium (K+) via pannexin1 (Panx1) channels. High extracellular ATP acts as a DAMP and binds to the purinergic receptor, P2X7 causing additional K+ efflux. Activation of NLRP3 involves oligomerization that results in activation of caspase-1 that converts pro-IL1β and pro-IL-18 into their mature forms. In addition, active caspase-1 cleaves Gasdermin D (GSDMD) into an N-terminus domain (GSDMD-N) and the autoinhibitory C-terminus domain (GSDMD-C). GSDMD-N binds to acidic phospholipids in the inner leaflet of the plasma membrane and oligomerizes to form pores that disrupt plasma membrane integrity, enabling release of IL-1β and IL-18 and inducing pyroptosis. The non-canonical pathway is activated by gram-negative bacteria or lipopolysaccharide (LPS) to activate caspase 4/5 in humans or caspase-11 in rodents that cleave GSDMD. The transient receptor protein channel 1 (TRPC1), a non-selective ion channel is also a substrate for caspase-11
Fig. 3 Mechanism of action of the NLRP3 inflammasome. In the canonical pathway, the priming step involves the recognition of pathogen-associated molecular pattern (PAMP) or a danger-associated molecular pattern (DAMP) by a pattern recognition receptor (PRR) or toll-like receptor (TLR), which recruits the adaptor protein myeloid differentiation primary response 88 (MYD88) into the receptor complex leading to phosphorylation of the inhibitor of nuclear factor-kB (NFκB) IκB through interaction with the p50 and p65 transcription factors. Activation of the NF-κB pathway causes the synthesis of pro-IL-1-β or pro-IL-18. NLRP3 is activated by lysosomal-mediated cathepsin B via lysosome rupture, reactive oxygen species (ROS), oxidized mitochondrial (Mt) DNA, altered Ca2+ concentration via mitochondrial dysfunction, and adenosine triphosphate (ATP) efflux and potassium (K+) via pannexin1 (Panx1) channels. High extracellular ATP acts as a DAMP and binds to the purinergic receptor, P2X7 causing additional K+ efflux. Activation of NLRP3 involves oligomerization that results in activation of caspase-1 that converts pro-IL1β and pro-IL-18 into their mature forms. In addition, active caspase-1 cleaves Gasdermin D (GSDMD) into an N-terminus domain (GSDMD-N) and the autoinhibitory C-terminus domain (GSDMD-C). GSDMD-N binds to acidic phospholipids in the inner leaflet of the plasma membrane and oligomerizes to form pores that disrupt plasma membrane integrity, enabling release of IL-1β and IL-18 and inducing pyroptosis. The non-canonical pathway is activated by gram-negative bacteria or lipopolysaccharide (LPS) to activate caspase 4/5 in humans or caspase-11 in rodents that cleave GSDMD. The transient receptor protein channel 1 (TRPC1), a non-selective ion channel is also a substrate for caspase-11CC BY · PubMed Central
Fig. 4 Modulation of NLRP3 signaling pathways. Upon stimulation, the tumor necrosis factor receptor 1 (TNFR1) and tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD) forms a complex in which receptor-interacting protein 1 (RIP1) acquires a polyubiquitin chain. Transforming growth factor beta-activated kinase 1 (TAK1, also known as mitogen-activated protein kinase kinase kinase 7 (MAP3K7)) binds to the polyubiquitin chain and activates the IκB kinase (IKK) complex (IKKα/IKKβ/NEMO (NF-kappa-B essential modulator)), leading to the activation of NF-κB. TAK1 also activates MAP kinases (MAPK) that activate the transcription factor, activator protein 1 (AP-1). NF-κB and AP-1 induce expression of inflammatory cytokines and antiapoptotic proteins. Inhibition of TAK1 promotes the assembly of the Panoptotic cell death complex. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) in association with Fs7-associated cell surface antigen (Fas)-associated death domain (FADD) and caspase-8 (Casp8) triggers nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome leading to activation of caspase-1 (CASP1) and cleavage of pro-interleukin (IL)-1β and pro-IL-18 into mature cytokines and caspase-1-mediated cleavage of Gasdermin D (GSDMD) resulting in release of IL-1β, IL-18, and apoptosis speck-like staining protein containing a CARD domain (ASC) specks. DEAD-box helicase 3 X-linked (DDX3X) promotes NLRP3 inflammasome activation and the pro-death cell-fate decision by interacting with the NLRP3 NACHT domain through its helicase (Heli) domain. Induction of stress granules causes the sequestration of DDX3X making it unavailable for NLRP3 inflammasome activation and thereby leading to a pro-survival state. Serine/threonine-protein kinase NEK7 interacts with the NACHT domain of NLRP3 inducing NLRP3 activation. NLRP3 is also activated by potassium efflux mediated by two-pore domain K+ (TWIK2) and voltage-gated potassium channel (Kv1.3) and pannexin1 (Panx1).
Fig. 4 Modulation of NLRP3 signaling pathways. Upon stimulation, the tumor necrosis factor receptor 1 (TNFR1) and tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD) forms a complex in which receptor-interacting protein 1 (RIP1) acquires a polyubiquitin chain. Transforming growth factor beta-activated kinase 1 (TAK1, also known as mitogen-activated protein kinase kinase kinase 7 (MAP3K7)) binds to the polyubiquitin chain and activates the IκB kinase (IKK) complex (IKKα/IKKβ/NEMO (NF-kappa-B essential modulator)), leading to the activation of NF-κB. TAK1 also activates MAP kinases (MAPK) that activate the transcription factor, activator protein 1 (AP-1). NF-κB and AP-1 induce expression of inflammatory cytokines and antiapoptotic proteins. Inhibition of TAK1 promotes the assembly of the Panoptotic cell death complex. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) in association with Fs7-associated cell surface antigen (Fas)-associated death domain (FADD) and caspase-8 (Casp8) triggers nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome leading to activation of caspase-1 (CASP1) and cleavage of pro-interleukin (IL)-1β and pro-IL-18 into mature cytokines and caspase-1-mediated cleavage of Gasdermin D (GSDMD) resulting in release of IL-1β, IL-18, and apoptosis speck-like staining protein containing a CARD domain (ASC) specks. DEAD-box helicase 3 X-linked (DDX3X) promotes NLRP3 inflammasome activation and the pro-death cell-fate decision by interacting with the NLRP3 NACHT domain through its helicase (Heli) domain. Induction of stress granules causes the sequestration of DDX3X making it unavailable for NLRP3 inflammasome activation and thereby leading to a pro-survival state. Serine/threonine-protein kinase NEK7 interacts with the NACHT domain of NLRP3 inducing NLRP3 activation. NLRP3 is also activated by potassium efflux mediated by two-pore domain K+ (TWIK2) and voltage-gated potassium channel (Kv1.3) and pannexin1 (Panx1).CC BY · PubMed Central
Fig. 5 Mechanism of NLRP1 and AIM2 activation. NLR family pyrin domain-containing protein 1 (NLRP1) has a unique function to find (FIIND) domain. The amino (N)-terminus inhibits the carboxy (C) terminus effector part of the protein, which contains the caspase-recruitment domain (CARD) domain, by a non-covalent interaction. A subsequent cleavage event of the N-terminus by a pathogenic trigger results in ubiquitination of the N-terminus inhibitory fragment by ubiquitin ligases, and the latter is degraded by the proteasome. The freed effector fragment induces apoptosis speck-like protein containing a CARD domain (ASC) speck formation, followed by caspase-1 activation and in turn processing of pro-IL-1β and IL-18 as well as cleavage of GasderminD (GSDMD). Secretion of the cytokines induces inflammation and GSDMD-induced pyroptosis. Absent in melanoma 2 (AIM2) inflammasome sensing of DNA triggers recruitment of the inflammasome adaptor ASC and caspase-1. Caspase-1 directly cleaves pro-IL-1β, pro-IL-18, and GSDMD. The amino (N)-terminus GSDMD-N fragment forms pores in the plasma membrane and initiates pyroptosis. IL-1β and IL-18 are released through the GSDMD pore leading to pyroptosis. GSDMD-C, carboxy-terminus GSDMD fragment
Fig. 5 Mechanism of NLRP1 and AIM2 activation. NLR family pyrin domain-containing protein 1 (NLRP1) has a unique function to find (FIIND) domain. The amino (N)-terminus inhibits the carboxy (C) terminus effector part of the protein, which contains the caspase-recruitment domain (CARD) domain, by a non-covalent interaction. A subsequent cleavage event of the N-terminus by a pathogenic trigger results in ubiquitination of the N-terminus inhibitory fragment by ubiquitin ligases, and the latter is degraded by the proteasome. The freed effector fragment induces apoptosis speck-like protein containing a CARD domain (ASC) speck formation, followed by caspase-1 activation and in turn processing of pro-IL-1β and IL-18 as well as cleavage of GasderminD (GSDMD). Secretion of the cytokines induces inflammation and GSDMD-induced pyroptosis. Absent in melanoma 2 (AIM2) inflammasome sensing of DNA triggers recruitment of the inflammasome adaptor ASC and caspase-1. Caspase-1 directly cleaves pro-IL-1β, pro-IL-18, and GSDMD. The amino (N)-terminus GSDMD-N fragment forms pores in the plasma membrane and initiates pyroptosis. IL-1β and IL-18 are released through the GSDMD pore leading to pyroptosis. GSDMD-C, carboxy-terminus GSDMD fragmentCC BY · PubMed Central
Fig. 6 Drugs targeting inflammasome signaling in MS and EAE. Interferon (IFN) regulates the transcriptional level of signal transducer and activator transcription 1 (STAT1) to suppress activity of the (NLR) family pyrin domain-containing 1 (NLRP1) and NLRP3 inflammasomes. STAT1 target gene products directly repress these inflammasomes. Additionally, IFN/STAT1 pathway increases IL-10 synthesis in macrophages, IL-10-mediated STAT3 activation, and the suppression of interleukin (IL)-1β precursor synthesis by activated STAT3. Ketotifen is an anti-histamine that inhibits mast cell degranulation to block activation of the NLRP3 inflammasome. MCC950 directly targets the NLRP3 NACHT domain and interferes with the Walker B motif function, preventing NLRP3 conformational change and oligomerization. IC100, a humanized monoclonal antibody, binds to apoptosis speck-like staining protein containing a CARD (ASC) and prevents recruitment of ASC into the NLRP3 signaling complex and blocks formation of ASC specks intracellular and extracellularly
Fig. 6 Drugs targeting inflammasome signaling in MS and EAE. Interferon (IFN) regulates the transcriptional level of signal transducer and activator transcription 1 (STAT1) to suppress activity of the (NLR) family pyrin domain-containing 1 (NLRP1) and NLRP3 inflammasomes. STAT1 target gene products directly repress these inflammasomes. Additionally, IFN/STAT1 pathway increases IL-10 synthesis in macrophages, IL-10-mediated STAT3 activation, and the suppression of interleukin (IL)-1β precursor synthesis by activated STAT3. Ketotifen is an anti-histamine that inhibits mast cell degranulation to block activation of the NLRP3 inflammasome. MCC950 directly targets the NLRP3 NACHT domain and interferes with the Walker B motif function, preventing NLRP3 conformational change and oligomerization. IC100, a humanized monoclonal antibody, binds to apoptosis speck-like staining protein containing a CARD (ASC) and prevents recruitment of ASC into the NLRP3 signaling complex and blocks formation of ASC specks intracellular and extracellularlyCC BY · PubMed Central

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  1. Kesavardhana S, RKS M, Kanneganti T-D. Caspases in cell death, inflammation, and pyroptosis, vol. 38; 2020. p. 567–95.

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Metadata

Authors
Govindarajan, V., de Rivero Vaccari, J. P., & Keane, R. W.
Affiliations
University of Miami (US)
Corresponding author
Keane, Robert W.
ORCID
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2020-09-02
Volume
17
Issue
1
Pages
260-260
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/s12974-020-01944-9
PMC
PMC7469327
OpenAlex
W3082497244
Cited by
110
References
103
Citations by year
2026: 12 · 2025: 15 · 2024: 23 · 2023: 26 · 2022: 21 · 2021: 10 · 2020: 3
FWCI
1.44
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute of Neurological Disorders and Stroke (R01NS113969-01)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
  • Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
multiple sclerosis, inflammasome, caspase-1, IL-1β, IL-18, pyroptosis, demyelination, autoimmune T cells, innate immunity, neuroinflammation, therapeutic target
MeSH terms
Animals, Humans, Immunologic Factors, Multiple Sclerosis, Signal Transduction, Cytokines, Caspases, Inflammasomes

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