title: The inflammasome sensor, NLRP3, regulates CNS inflammation and demyelination via caspase-1 and interleukin-18.
abstract: Inflammation is increasingly recognized as an important contributor to a host of CNS disorders; however, its regulation in the brain is not well delineated. Nucleotide-binding domain, leucine-rich repeat, pyrin domain containing 3 (NLRP3) is a key component of the inflammasome complex, which also includes ASC (apoptotic speck-containing protein with a card) and procaspase-1. Inflammasome formation can be triggered by membrane P2X(7)R engagement leading to cleavage-induced maturation of caspase-1 and interleukin-1β (IL-1β)/IL-18. This work shows that expression of the Nlrp3 gene was increased >100-fold in a cuprizone-induced demyelination and neuroinflammation model. Mice lacking the Nlrp3 gene (Nlrp3(-/-)) exhibited delayed neuroinflammation, demyelination, and oligodendrocyte loss in this model. These mice also showed reduced demyelination in the experimental autoimmune encephalomyelitis model of neuroinflammation. This outcome is also observed for casp1(-/-) and IL-18(-/-) mice, whereas IL-1β(-/-) mice were indistinguishable from wild-type controls, indicating that Nlrp3-mediated function is through caspase-1 and IL-18. Additional analyses revealed that, unlike the IL-1β(-/-) mice, which have been previously shown to show delayed remyelination, Nlrp3(-/-) mice did not exhibit delayed remyelination. Interestingly, IL-18(-/-) mice showed enhanced remyelination, thus providing a possible compensatory mechanism for the lack of a remyelination defect in Nlrp3(-/-) mice. These results suggest that NLRP3 plays an important role in a model of multiple sclerosis by exacerbating CNS inflammation, and this is partly mediated by caspase-1 and IL-18. Additionally, the therapeutic inhibition of IL-18 might decrease demyelination but enhance remyelination, which has broad implications for demyelinating diseases.
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Sushmita
authors.initials: S
authors.lastname: Jha
authors.forename: Siddharth Y
authors.initials: SY
authors.lastname: Srivastava
authors.forename: W June
authors.initials: WJ
authors.lastname: Brickey
authors.forename: Heather
authors.initials: H
authors.lastname: Iocca
authors.forename: Arrel
authors.initials: A
authors.lastname: Toews
authors.forename: James P
authors.initials: JP
authors.lastname: Morrison
authors.forename: Vivian S
authors.initials: VS
authors.lastname: Chen
authors.forename: Denis
authors.initials: D
authors.lastname: Gris
authors.forename: Glenn K
authors.initials: GK
authors.lastname: Matsushima
authors.forename: Jenny P-Y
authors.initials: JP
authors.lastname: Ting
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D020170:Caspase 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D003711:Demyelinating Diseases / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D058847:Inflammasomes / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D020382:Interleukin-18 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D018836:Inflammation Mediators; D020382:Interleukin-18; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D020170:Caspase 1