Biology Reference
In-Depth Information
NLRP1 inflammasome
NLRP1 differs from other NLR proteins by having two signal transduc-
tion domains; that is, a pyrin domain and CARD
[77,82]
. This inflamma-
some was first identified in humans before being recognized in murine
cells
[93,94]
. However, unlike humans, who have a single
NLRP1
gene,
mice have three tandem paralogs,
Nlrp1a, N1rp1b,
and
Nlrp1c-ps
(also
known as
Nalp1a, Nalp1b,
and
Nalp1c,
respectively)
[81,82,95]
. Further-
more, different strain-specific alleles exist for
Nlrp1b,
and the activating
genetic variant is resistant to anthrax induction and thus led to the iden-
tification of NLRP1b as the sensor for
Bacillus anthracis
lethal toxin
[95]
.
Nonetheless, the role of NLRP1 in immune responses remains poorly
understood.
Its relevance to human disease, however, is highlighted by the association of
variations in the gene encoding NLRP1 with vitiligo, type 1 diabetes, Addi-
son's disease, rheumatoid arthritis, and Alzheimer's disease
[96]
.
NLRP3 inflammasome
Several observations have shed light on the critical role of the NLRP3 inflam-
masome on the activity of caspase 1 and release of IL-1
[77,80]
.
NLRP3
gain-
of-function mutations lead to cryopyrin-associated periodic syndromes,
which are treatable with inhibitors of IL-1β-mediated signaling
[80,97]
.
The NLRP3 inflammasome is activated by a plethora of microbial stimuli,
including MDP, bacterial RNA, the double-stranded RNA analog poly(I:C),
lipopolysaccharide, microbial lipopeptide, the imiquimod R-837, and the
synthetic resiquimod
[77,82]
. NLRP3 can also be activated by endogenous
stimuli and particulate matter, such as uric acid, cholesterol, hydroxyapa-
tite crystals, silica, aluminum salts, asbestos, malarial hemozoin, amyloid
deposits, and fatty acids
[77,82]
. Evidence indicates that most of these are
not directly sensed by, or activate, the NLRP3 inflammasome. Furthermore,
under conditions in which the autophagic pathway is compromised, stimu-
lation with pathogen-associated molecular patterns induces activation of
the NLRP3 inflammasome and more production of pro-IL-1β, suggesting a
role for autophagy
[98,99]
.
435
NLRC4 inflammasome
NLRC4 is important for the activation of caspase 1 in macrophages infected
with pathogenic bacteria, such as
Salmonella, Legionella,
and
Pseudomo-
nas aeruginosa
[77,80,82]
. Flagellin, the main component of the bacte-
rial flagellum, is critical for activation of the NLRC4 inflammasome
[100]
.
Data suggest that NLRC4 can also be activated
[100]
by flagellin-deficient
Salmonella
or
Shigella
—the mechanism of sensing nonetheless remains
unknown
[82]
. NLRC4 can also be activated by another type of NLR protein,
NAIP proteins
[82,96]
. An interesting characteristic of the NLRC4 inflam-
masome is that it remains active in macrophages that have been tolerized
to TLR stimulation, the mechanisms of which remain unknown
[82,96]
.
Activation of this inflammasome leads to secretion of IL-1 and IL-18
[80]
. In
addition, activators of the NLRC4 inflammasome also induce pyroptosis, a
form of caspase 1-dependent cell death with features of both apoptosis and
necrosis
[82]
.
Search WWH ::
Custom Search