The NLRP3 inflammasome
The NLRP3 inflammasome is involved in caspase-1 activation and the
release of proinflammatory cytokines IL-1β/IL-18 in response to
infection and cellular damage (Kelley, Jeltema, Duan & He, 2019). In
response to an attack, pattern-recognition receptors (PRRs) activate the
innate immune system, which is the body’s initial line of defense. Even
though NLRP3 inflammasome activation is still poorly understood, there
are several factors at play, including pathogen-associated molecular
patterns (PAMPs), damage-associated molecular patterns (DAMPs), and a
second signal that stimulates the assembly of NLRP3, ASC, and
pro-caspase-1 into the NLRP3 inflammasome complex via multiple
ROS-producing pathways (Abais, Xia, Zhang, Boini & Li, 2015). When
these patterns are activated, it sets off a cascade of events that
clears the infection and repairs any harm it has caused. Inflammasome
activation results in the release of cytokines such as IL-1β and IL-18,
as well as the generation of pyroptosis, an inflammatory form of cell
death (Kelley, Jeltema, Duan & He, 2019; Sharma & Kanneganti, 2016).
Studies have shown that pathogen-derived ligands include nucleic acids,
microbial wall components, and toxitoxins activate NLRP3. NLRP3 has also
been shown to be activated by environmental crystalline contaminants
such silica, asbestos, and alum (Man & Kanneganti, 2015). When SAH
boosted TREM-1 expression, NLRP3 inflammasome components (NLRP3, ASC),
cleaved caspase-1, mature IL-1β, and mature IL-18 were all elevated into
their active forms as well (Xu et al., 2021). Multiple studies have
shown that SAH activates the NLRP3 inflammasome, which has been shown to
be inhibited in those who have had the condition, For example, in both
the early and delayed phases after SAH. (Dodd, Noda, Martinez, Hosaka &
Hoh, 2021) found NLRP3 mediated neuroinflammation to be associated with
cerebrovascular impairment. EBI and DCI therapies could benefit from the
use of MCC950 and other NLRP3 inhibitors. (Xu et al., 2019b) found that
following SAH, the levels of APJ and AMPK rose. Despite the fact that
endogenous APJ and AMPK were increased, this was not enough to reduce
NLRP3 inflammasome activity or inflammatory cytokines in the body, as
previously described. Exogenous apelin-13 increased AMPK levels, which
prevented the NLRP3 inflammasome from activating and decreased Bip,
cleaved caspase-1, IL-1β, TNF-α, MPO, and ROS levels while
simultaneously boosting AMPK levels. To make matters worse, the AMPK
inhibitor upregulated the production of NLRP3, cleaved caspase-1, IL-1β,
TNF-α, MPO, and ROS in addition to negating the good effects of
anti-inflammatory and anti-oxidative stress, which made conditions to
further worsen. Microglial modulation has been linked to favorable
effects on the cerebrovascular system in studies by (Dodd, Noda,
Martinez, Hosaka & Hoh, 2021), however these studies have not
demonstrated that NLRP3 suppression alleviates cerebrovascular
dysfunction through this mechanism. NLRP3-mediated neuroinflammation is
frequently attributed to microglia as the primary cause (Luo, Reis &
Chen, 2019).