The NLRP3 Inflammasome: A Possible Therapeutic Target for Treatment of Stroke

Chapter
Part of the Springer Series in Translational Stroke Research book series (SSTSR)

Abstract

Ischemic stroke is a complex systemic disease causing severe long-term disability and death worldwide. Experimental and clinical data have demonstrated that inflammation is a major component of ischemic stroke pathobiology. The post-ischemic neuroinflammatory response is characterized by microglial and astro-glial activation and increased expression of inflammatory mediators. Recent findings have provided insight into a newly discovered inflammatory mechanism that contributes to neuronal and glial cell death in neurodegenerative diseases and stroke mediated by inflammasomes. Interestingly, of inflammasomes described to date, NLRP3 (nucleotide-binding domain (NOD)-like receptor protein 3) inflammasome is the best characterized multi-protein complexes and most strongly associated with sterile inflammation. In this chapter, we discuss in detail the prominent contribution and regulation of NLRP3-inflammasome activation in the pathophysiology of ischemic stroke. Furthermore, provide recent developments on the potential of NLRP3 inhibitors in the therapeutic management of stroke outcomes. The significant contribution of regulatory mechanisms of NLRP3 inflammasome with the development of stroke, may improve our understanding of NLRP3 inhibition for developing future therapies and novel drug targets for stroke.

Keywords

NLRP3 Inflammasome Ischemic stroke Inflammation NOD-like receptor protein Neuronal death Inhibitors 

Abbreviations

Amyloid beta

ADP

Adenosine di phosphate

AIM2

Absence in melanoma

AMD

Age-related macular degeneration

AMPK

AMP-activated protein kinase

ASC

Apoptosis-associated speck like

ASK-1

Apoptosis signal-regulating kinase

ASICS

Acid-sensing ion channels

ATP

Adenosine di phosphate

BBB

Blood brain barrier

BBG

Brilliant blue G

BHB

β-hydroxybutyrate

BRCC3

BRCA1/BRCA2-containing complex, subunit 3

BTK

Bruton’s tyrosine kinase

CaSR

Calcium sensing receptor

CB2R

Cannabinoid receptor 2

CLR

C-type lectin receptor

CM

Carbon monoxide

Cox2

Cyclooxygenase-2

CNS

Central nervous system

CRID

Cytokine release inhibitory drugs

CXCL1

Chemokine (C-X-C motif) ligand-1

DAMP

Damage-associated molecular patterns

DPI

Diphenylene iodonium

DUBs

Deubiquitinating enzymes

eMCAO

Embolic middle cerebral artery occlusion

EAE

Experimental autoimmune encephalomyelitis

EGCG

Epigallocatechin gallate

EP-4

Prostaglandin E2 receptor 4

ER-stress

Endoplasmic reticulum stress

FFA

Free fatty acid

FBXL2

SCF complex subunit F-box L2

GFAP

Glial fibrillary acidic protein

GLUT1

Glucose transporter-1

GPR6CA

G protein-coupled receptor family C group 6 member A

GSDMD

Gasdermin D

HCA

Hydroxy-carboxylic acid receptor 2

HIF-α

Hypoxia inducible factor-1 alpha

HRECs

Human retinal endothelial cells

HSP90

Heat shock protein 90

ICH

Intracerebral hemorrhage

IFN

Interferon

IFNAR

Interferon-alpha/beta receptor

IL-1β

Interleukin 1 beta

IP3

Inositol trisphosphate

IER-1

Inositol-requiring 1

iNOS

Inducible nitric oxide synthase

IRAK

Interleukin-1 receptor-associated kinase 1

JAC

Janus kinase

JNK

c-jun-N-terminal kinase

KO

Knock-out

LPS

Lipopolysaccharide

LRR

Leucine rich repeat domain

MAP

Mitogen activated protein

MAVS

Mitochondrial anti-viral signaling protein

MCAO

Middle cerebral artery occlusion

MFGE8

Milk fat globule-EGF 8

MI

Myocardial infarction

MAPK

Mitogen-activated protein kinase

miRNA

Micro ribonucleic acid

mtROS

Mitochondrial Reactive oxygen species

MCT

Monocarboxylate transporter 1

MMP-9

Matrix metalloproteinase 9

MNS

3,4-Methylenedioxy-β-nitrostyrene

MRI

Magnetic resonance imaging

MyD-88

Myeloid differentiation primary response 88

NADPH

Nicotinamide adenine dinucleotide phosphate-oxidase

NAD

Nicotinamide adenine dinucleotide phosphate

NADH

Nicotinamide adenine dinucleotide phosphate

NBD

Nucleotide-binding domain

NFκB

Nuclear factor kappa-B

NLR

Nucleotide-binding oligomerization domain like receptor

NLRP

NOD-like receptor proteins

NMDA

N-methyl-D-Aspartate

NOD

Nucleotide-binding oligomerization domain

NOX

Nicotinamide adenine dinucleotide phosphate oxidase

OGD

Oxygen glucose deprivation

Pal-BSA

Palmitate coupled to bovine serum albumin

PAMP

Pathogen-associated molecular patterns

PERK

dsRNA-activated protein kinase-like ER kinase

PGE2

Prostaglandin E2

PKA

Protein kinase A

PLC

Phospholipase c

PPA2

Pyrophosphatase 2

PPAR-γ

Peroxisome proliferator-activated receptor-γ

PRR

Pattern recognition receptor

PTP

Phospho-tyrosine phosphatases

P2X7R

P2X purinoceptor 7

RKIP

Raf-1 kinase inhibitory protein

ROS

Reactive oxygen species

SAR

Structure activity relationship

Ser

Serine

SGT1

Suppressor of g2 allele of skp1

SLC

Solute carriers

SCF

SKP1-cullin-F-box protein

SUR1

Sulfonylurea receptor 1

STAT

Signal transducers and activators of transcription

TAK1

Transforming growth factor beta-activated kinase 1

tMCAO

Transient middle cerebral artery occlusion

Thr

Thioredoxin

TLR

Toll-like receptor

TNF-α

Tumor necrotizing factor α

TRIF

TIR-domain-containing adapter-inducing interferon-β

Trpm4

Transient receptor potential melastatin 4

Trx

Thioredoxin

TXNIP

Thioredoxin interacting protein

WT

Wild type

Notes

Acknowledgements

This chapter was supported by R01NS097800-01 to Tauheed Ishrat.

Disclosure of conflict of interest: None

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Anatomy and Neurobiology, College of MedicineUniversity of Tennessee Health Science CenterMemphisUSA
  2. 2.Neuroscience Research CenterShahid Beheshti University of Medical SciencesTehranIran

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