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Page 158 Harry et al. Neuroimmunol Neuroinflammation 2020;7:150-65 I http://dx.doi.org/10.20517/2347-8659.2020.07

such as asbestos, silica crystals, aluminum salts, and polystyrene nanoparticles [175-178] , and aberrant proteins,
such as extracellular Ab [179] , thereby contributing to a broad range of common inflammatory pathologies
and chronic inflammation.

The NLRP3 inflammasome responds to metabolic regulation [180] and has been increasingly recognized
as a bridge between mitochondrial damage sensing and pro-inflammatory signaling within monocytes,
including microglia [181,182] . Unlike most inflammasomes, NLRP3 typically requires a two-step activation
and it is this process for which there is mounting evidence that mitochondrial damage plays a contributing
role [101] . Activation of TLR, tumor necrosis factor receptor, or interleukin-1 receptor (IL-1R) initiates an
intracellular cascade of effects, including activation of NF-kB. This upregulates NLRP3 and pro-IL-1b
within the cell and facilitates post-transcriptional changes to NLRP3 to free ubiquitinated binding sites
by BRCC3 (BRCA1/2-containing complex subunit 3) [176,183,184] . Delivery of a secondary “trigger” such
as PAMPs, DAMPs, or intact pathogens to the “primed” cell causes the release of the repressed state of
NLRP3. Upon release, NLRP3 activates the inflammasome forming a multiprotein complex comprised of
the cytosolic sensor NLRP3, ASC, and caspase 1 [185] . Caspase 1 facilitates the cleavage of the pro-forms of
IL-1b and IL-18 [186] , resulting in the release of mature protein [187] . The release of active IL-1 family cytokines
is normally related to pyroptotic cell death; however, in the absence of cell death, hyperactivity of cells and
the recruitment of a process dependent on plasma membrane-localized pores can result in similar protein
release [188,189] . While inflammasome activation is an efficient producer of mature IL-1b, inflammasome
independent mechanisms exist, including cathepsin B or caspase 11 dependent pathways [190,191] ,
bacterial pore-forming toxins, and extracellular ATP [177] . Thus, an upregulation of mature IL-1b does
not automatically indicate an inflammasome mechanism. In addition to the release of inflammatory
factors, the physical release of ASC specks into the extracellular environment represents a stimulus for
activating phagocytic cells in the immediate environment, thus contributing to a prolonged propagation of
inflammation [192] or other biological responses [193] .

Induction of mitophagy, the process by which cells clear damaged mitochondria, has been implicated in
inhibition of NLRP3 signaling [194] . Release of oxidized mitochondrial DNA (mtDNA) produced during
the priming stage [195,196] can interact with the NLRP3 receptor and induce inflammasome activation.
Nakahira et al. [196] reported that inhibition of mitophagy in macrophages heightened the NLRP3
inflammasome activation in parallel with uncleared mitochondrial DNA released into the cytosol. The
mitochondrial cytidine/uridine monophosphate kinase-2 (CMPK2) is a nucleotide kinase required for
mtDNA synthesis and production of oxidized mtDNA fragments. These fragments can act as activating
ligands for the NLRP3 inflammasome complex [197] . In addition, the release of mtROS triggered by small
molecule inhibition of complex I and III has been associated with NLRP3 inflammasome activation [198] .
The association between mtROS as a trigger for NLRP3 inflammasome activation remains controversial
given potential off-target effects of mtROS inhibitors. While studies have reported a role for mtROS in
NLRP3 inflammasome activation, other conflicting studies have been reported. At least one study reported
[199]
that mtROS inhibitors do not block the secondary activation step, but rather the initial priming step .
Apart from acting as an activator of NLRP3, mitochondria can act as a docking system for inflammasome
assembly. This interaction is driven by the externalization of mitochondrial lipid cardiolipin from the inner
[200]
membrane to the outer membrane, which then independently interacts with caspase-1 and NLRP3 .
NLRP3 inflammasome activation in microglia has gained attention as a contributing mechanism in several
neuroinflammatory disease pathologies including Alzheimer’s disease, amyotrophic lateral sclerosis,
multiple sclerosis, and Parkinson’s disease [201-205] . While much is similar between the biochemistries of
microglia and macrophages, differences in inflammasome activation have been reported. For example,
exposure of microglia cells to the antioxidant NAC did not affect LPS priming yet inhibited Ab 1-42
peptide stimulation of caspase-1 dependent IL-1b secretion [202] . While microglia show similar expression