The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins

Abstract

Microglial NLRP3 inflammasome activation is emerging as a key contributor to neuroinflammation during neurodegeneration. Pathogenic protein aggregates such as β‐amyloid and α‐synuclein trigger microglial NLRP3 activation, leading to caspase‐1 activation and IL‐1β secretion. Both caspase‐1 and IL‐1β contribute to disease progression in the mouse SOD1G93A model of amyotrophic lateral sclerosis (ALS), suggesting a role for microglial NLRP3. Prior studies, however, suggested SOD1G93A mice microglia do not express NLRP3, and SOD1G93A protein generated IL‐1β in microglia independent to NLRP3. Here, we demonstrate using Nlrp3‐GFP gene knock‐in mice that microglia express NLRP3 in SOD1G93A mice. We show that both aggregated and soluble SOD1G93A activates inflammasome in primary mouse microglia leading caspase‐1 and IL‐1β cleavage, ASC speck formation, and the secretion of IL‐1β in a dose‐ and time‐dependent manner. Importantly, SOD1G93A was unable to induce IL‐1β 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‐1β secretion. Microglial NLRP3 upregulation was also observed in the TDP‐43Q331K 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 SOD1G93A‐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.

Mechanisms of Immune Activation by c9orf72-Expansions in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

“…Microglia were found to secrete IL-1β when stimulated with TDP-43 protein, and the effect was again abolished by the addition of MCC950 (Deora et al, 2019). This demonstration of the activation of the NLRP3 inflammasome in multiple in vivo and in vitro models of ALS, and the subsequent reduction in IL-1β secretion with an NLRP3 inhibitor suggests a commonality that may potentially be utilized as a novel target for therapeutics.…”

Clemastine improves hypomyelination in rats with hypoxic–ischemic brain injury by reducing microglia-derived IL-1β via P38 signaling pathway

“…Thus, preventing the excessive release of IL-1β is necessary. NLRP3 is the upstream signal factor controlling the release of IL-1β [37]; thus, inhibiting its release can reduce tissue damage [38]. MCC950 is a selective inhibitor of NLRP3 which reduces the release of IL-1β in vivo [39].…”

The NLRP3 inflammasome in traumatic brain injury: potential as a biomarker and therapeutic target

“…The increase in these pro-inflammatory proteins ultimately leads to pyroptosis neurons has been disputed, its expression has consistently been found in microglia and astrocytes [59][60][61]. As such, NLRP3 activity is receiving growing interest as a contributor to various CNS conditions in which gliamediated neuroinflammation has been associated with disease progression such as Alzheimer's disease, stroke, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and pneumococcal meningitis [62][63][64][65][66][67][68]. Although the NLRP3 inflammasome was not investigated in the context of TBI until 2013, there is now mounting evidence implicating this inflammasome as a critical component in the pathogenesis of the secondary damage that occurs following TBI.…”