This study provides theoretical support to the therapeutic evaluation of RAPA and MCC950 to make the mammalian targets of RAPA and NLRP3 the therapeutic targets of MS.
Several lines of evidence point out the relevance of nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome as a pivotal player in the pathophysiology of several neurological and psychiatric diseases (i.e., Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis, and major depressive disorder), metabolic disorders (i.e., obesity and type 2 diabetes) and chronic inflammatory diseases (i.e., intestinal inflammation, arthritis, and gout).
PBM analysis showed that MS cells express higher level of inflammasome genes than HD ones, and are more prone to respond to a classical NLRP3 stimulus than HD.
The NLRP3 inflammasome is associated with the onset and progression of autoinflammatory and autoimmune diseases, including metabolic disorders, multiple sclerosis, inflammatory bowel disease, and cryopyrin-associated periodic fever syndrome.
Altogether, our data evidence that the NLRP3 gain-of-function promotes a Th2-related response, a pathway that could be better explored in the treatment of multiple sclerosis.
Microglia A20 deficiency also exacerbates multiple sclerosis (MS)-like disease, due to hyperactivation of the Nlrp3 inflammasome leading to enhanced interleukin-1β secretion and CNS inflammation.
This case-control study was performed to determine the association of NLRP3 genetic variants and differential expression with MS. We analysed four common single nucleotide polymorphisms (SNPs) of NLRP3 (rs-10754558, rs-35829419, rs-3806265, rs-4612666) in a group of 150 Iranian patients with relapsing-remitting MS (RRMS) in comparison with 100 healthy controls.
Together, our findings suggest that inhibition of NLRP3 inflammasome activation may be a potential therapeutic approach to alleviate MS-associated CNP and disease relapses in patients with RR-MS.
Experiments with the mouse model of MS, experimental autoimmune encephalomyelitis (EAE), specifically describe the NLRP3 inflammasome as critical and necessary to disease development.
To this end, we treated experimental autoimmune encephalomyelitis (EAE) mice model of multiple sclerosis (MS) with the conditioned medium or purified exosomes/microvesicles (EMVs) obtained from relapsing-remitting-MS patients human periodontal ligament stem cells (hPDLSCs) and investigated the regulation of NALP3 inflammasome.
Collectively, these results suggest that JC-171 is a selective NLRP3 inflammasome inhibitor with biological activity in vivo, thus strongly encouraging further development of this lead compound as a potential therapeutic agent for human MS.
In summary, we reported for the first time that PRO therapy causes polarization of M2 microglia, attenuation of M1 phenotype, and suppression of NLRP3 inflammasome in a CPZ-induced demyelination model of MS.
For example, the NLR family, pyrin domain containing 3 (NLRP3) inflammasome, which is known to sense a wide variety of pathogens, can also change the course of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS).
In the present study, we show that expression of the inflammasome related genes, NLRP3, caspase-1, IL-1β and the IL-1β/IL-1Ra ratio, was increased in PBMC from MS patients compared to healthy controls (HC).
Thus, our data demonstrate that human P2X7R-mediated NLRP3 inflammasome activation is regulated by activated CD4+CD45RO+ memory T cells, and provide new information on the mechanisms mediating the therapeutic effects of IFNβ in MS.