| First Author | Deora V | Year | 2020 |
| Journal | Glia | Volume | 68 |
| Issue | 2 | Pages | 407-421 |
| PubMed ID | 31596526 | Mgi Jnum | J:287837 |
| Mgi Id | MGI:6382226 | Doi | 10.1002/glia.23728 |
| Citation | Deora V, et al. (2020) The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins. Glia 68(2):407-421 |
| abstractText | Microglial NLRP3 inflammasome activation is emerging as a key contributor to neuroinflammation during neurodegeneration. Pathogenic protein aggregates such as beta-amyloid and alpha-synuclein trigger microglial NLRP3 activation, leading to caspase-1 activation and IL-1beta secretion. Both caspase-1 and IL-1beta contribute to disease progression in the mouse SOD1(G93A) model of amyotrophic lateral sclerosis (ALS), suggesting a role for microglial NLRP3. Prior studies, however, suggested SOD1(G93A) mice microglia do not express NLRP3, and SOD1(G93A) protein generated IL-1beta in microglia independent to NLRP3. Here, we demonstrate using Nlrp3-GFP gene knock-in mice that microglia express NLRP3 in SOD1(G93A) mice. We show that both aggregated and soluble SOD1(G93A) activates inflammasome in primary mouse microglia leading caspase-1 and IL-1beta cleavage, ASC speck formation, and the secretion of IL-1beta in a dose- and time-dependent manner. Importantly, SOD1(G93A) was unable to induce IL-1beta secretion from microglia deficient for Nlrp3, or pretreated with the specific NLRP3 inhibitor MCC950, confirming NLRP3 as the key inflammasome complex mediating SOD1-induced microglial IL-1beta secretion. Microglial NLRP3 upregulation was also observed in the TDP-43(Q331K) ALS mouse model, and TDP-43 wild-type and mutant proteins could also activate microglial inflammasomes in a NLRP3-dependent manner. Mechanistically, we identified the generation of reactive oxygen species and ATP as key events required for SOD1(G93A) -mediated NLRP3 activation. Taken together, our data demonstrate that ALS microglia express NLRP3, and that pathological ALS proteins activate the microglial NLRP3 inflammasome. NLRP3 inhibition may therefore be a potential therapeutic approach to arrest microglial neuroinflammation and ALS disease progression. |
