Activating cannabinoid receptor 2 alleviates pathogenesis of experimental autoimmune encephalomyelitis via activation of autophagy and inhibiting NLRP3 inflammasome.
Reads0
Chats0
TLDR
Whether autophagy is involved in the beneficial effect of CB2R on EAE is examined and the mechanism with a focus on inflammasome activation is explored.Abstract:
SummaryAims
Activation of cannabinoid receptor 2 (CB2R) has been reported to ameliorate the pathogenesis of experimental autoimmune encephalomyelitis (EAE). In this study, we examined whether autophagy is involved in the beneficial effect of CB2R on EAE and explored the mechanism with a focus on inflammasome activation.
Methods
EAE severity was analyzed with clinical score and histological score stained by hematoxylin and eosin or luxol fast blue in spinal cord. Immunoblot analysis was conducted to detect proteins of NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-related caspase-1 (Casp-1) and the maturation of interleukin (IL)-1β as well as autophagy-related light chain 3 (LC3), and Beciln 1 both in vivo and in vitro. Reverse transcription and real-time PCR were used to detect mRNA of NLRP3, IL-1β and Casp-1. Autophagy-related gene 5 (ATG5)-specific siRNA was transiently transfected in BV2 microglia, and immunofluorescence staining was carried out to detect the expression of NLRP3, caspase recruitment domain (ASC), and pro-caspase-1.
Results
The current data indicated that deleting CB2R decreased the expression of LC3-II/LC3-I ratio, Beclin 1 and increased caspase-1 activation and IL-1β production in the spinal cord of EAE mice, whereas activation of CB2R with a specific agonist HU-308 induced inverse effects. Further study indicated that HU-308 could promote autophagy and inhibit expression and activation of NLRP3 inflammasome in BV2 microglia. Blocking autophagy by ATG5-specific siRNA dismissed the effort of CB2R in mediating NLRP3 inflammasome in vitro.
Conclusion
Collectively, our results demonstrated for the first time that CB2R plays a protective role in EAE through promoting autophagy and inhibiting NLRP3 inflammasome activation.read more
Citations
More filters
Journal ArticleDOI
NLRP3 inflammasome and its inhibitors: a review.
TL;DR: The present review will describe the structure and mechanisms of activation of the NLRP3 inflammasome, its association with various auto-immune and auto-inflammatory diseases, and the state of research into NLRP2 inflammaome inhibitors.
Journal ArticleDOI
Pharmacological Inhibitors of the NLRP3 Inflammasome.
TL;DR: This paper will review the various pharmacological inhibitors of the NLRP3 inflammasome and will also discuss their mechanism of action.
Journal ArticleDOI
New insights into the interplay between autophagy, gut microbiota and inflammatory responses in IBD.
TL;DR: This review describes the latest researches on the mechanisms by which dysfunctional autophagy leads to disrupted intestinal epithelial function, gut dysbiosis, defect in anti-microbial peptide secretion by Paneth cells, endoplasmic reticulum stress response and aberrant immune responses to pathogenic bacteria.
Journal ArticleDOI
Autophagy and Alzheimer's Disease: From Molecular Mechanisms to Therapeutic Implications.
Md. Sahab Uddin,A. Stachowiak,Abdullah Al Mamun,Nikolay T. Tzvetkov,Shinya Takeda,Atanas G. Atanasov,Leandro Bueno Bergantin,Mohamed M. Abdel-Daim,Adrian M. Stankiewicz +8 more
TL;DR: Mechanisms and genes linking autophagy and AD, i.e., the mTOR pathway, neuroinflammation, endocannabinoid system, ATG7, BCL2, BECN1, CDK5, CLU, CTSD, FOXO1, GFAP, ITPR1, MAPT, PSEN1, SNCA, UBQLN 1, and UCHL1 are discussed.
Journal ArticleDOI
Autophagy and Microglia: Novel Partners in Neurodegeneration and Aging.
TL;DR: Evidence is provided of how autophagy may affect microglial phagocytosis of apoptotic cells, amyloid-β, synaptic material, and myelin debris, and regulate the progression of age-associated neurodegenerative diseases, including ischemia/stroke, Alzheimer's, Parkinson's, and Huntington’s diseases, and multiple sclerosis.
References
More filters
Journal ArticleDOI
Inflammasomes in health and disease
TL;DR: The functions of the different inflammasome complexes are reviewed and how aberrations in them are implicated in the pathogenesis of human diseases are discussed.
Journal ArticleDOI
Activation of Autophagy by Inflammatory Signals Limits IL-1β Production by Targeting Ubiquitinated Inflammasomes for Destruction
Chong-Shan Shi,Kevin Shenderov,Ning Na Huang,Juraj Kabat,Mones Abu-Asab,Katherine A. Fitzgerald,Alan Sher,John H. Kehrl +7 more
TL;DR: It is shown that the induction of AIM2 or NLRP3 inflammasomes in macrophages triggered activation of the G protein RalB and autophagosome formation, which indicates that autophagy accompaniesinflammasome activation to temper inflammation by eliminating active inflammaomes.
Journal ArticleDOI
Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells
María Salazar,Arkaitz Carracedo,Íñigo J. Salanueva,Sonia Hernández-Tiedra,Mar Lorente,Ainara Egia,Patricia Vázquez,Cristina Blázquez,Sofia Torres,Stéphane Garcia,Jonathan Nowak,Gian Maria Fimia,Mauro Piacentini,Francesco Cecconi,Pier Paolo Pandolfi,Luis González-Feria,Juan L. Iovanna,Manuel Guzmán,Patricia Boya,Guillermo Velasco +19 more
TL;DR: It is demonstrated that delta(9)-tetrahydrocannabinol (THC), the main active component of marijuana, induces human glioma cell death through stimulation of autophagy and evidence is provided that cannabinoid administration may be an effective therapeutic strategy for targeting human cancers.
Journal ArticleDOI
Cannabinoids control spasticity and tremor in a multiple sclerosis model.
David Baker,Gareth Pryce,J L Croxford,Peter Brown,Roger G. Pertwee,John W. Huffman,L Layward +6 more
TL;DR: It is shown that cannabinoid (CB) receptor agonism quantitatively ameliorated both tremor and spasticity in diseased mice, providing a rationale for patients' indications of the therapeutic potential of cannabis in the control of the symptoms of multiple sclerosis.
Related Papers (5)
A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases
Rebecca C. Coll,Avril A. B. Robertson,Jae Jin Chae,Sarah C. Higgins,Raúl Muñoz-Planillo,Marco Inserra,Irina Vetter,Lara S. Dungan,Brian G. Monks,Andrea Stutz,Daniel E. Croker,Mark S. Butler,Moritz Haneklaus,Caroline E. Sutton,Gabriel Núñez,Eicke Latz,Daniel L. Kastner,Kingston H. G. Mills,Seth L. Masters,Kate Schroder,Mark E. Cooper,Luke A. J. O'Neill +21 more