NLRP3 inflammasome plays a key role in the regulation of intestinal homeostasis.
BACKGROUND
Attenuated innate immune responses to the intestinal microbiota have been linked to the pathogenesis of Crohn's disease (CD). Recent genetic studies have revealed that hypofunctional mutations of NLRP3, a member of the NOD-like receptor (NLR) superfamily, are associated with an increased risk of developing CD. NLRP3 is a key component of the inflammasome, an intracellular danger sensor of the innate immune system. When activated, the inflammasome triggers caspase-1-dependent processing of inflammatory mediators, such as IL-1β and IL-18.


METHODS
In the current study we sought to assess the role of the NLRP3 inflammasome in the maintenance of intestinal homeostasis through its regulation of innate protective processes. To investigate this role, Nlrp3(-/-) and wildtype mice were assessed in the dextran sulfate sodium and 2,4,6-trinitrobenzenesulfonic acid models of experimental colitis.


RESULTS
Nlrp3(-/-) mice were found to be more susceptible to experimental colitis, an observation that was associated with reduced IL-1β, reduced antiinflammatory cytokine IL-10, and reduced protective growth factor TGF-β. Macrophages isolated from Nlrp3(-/-) mice failed to respond to bacterial muramyl dipeptide. Furthermore, Nlrp3-deficient neutrophils exhibited reduced chemotaxis and enhanced spontaneous apoptosis, but no change in oxidative burst. Lastly, Nlrp3(-/-) mice displayed altered colonic β-defensin expression, reduced colonic antimicrobial secretions, and a unique intestinal microbiota.


CONCLUSIONS
Our data confirm an essential role for the NLRP3 inflammasome in the regulation of intestinal homeostasis and provide biological insight into disease mechanisms associated with increased risk of CD in individuals with NLRP3 mutations.
Hirota
Simon A
SA
Gastrointestinal Research Group, University of Calgary, Calgary, AB, Canada. simon.hirota@ucalgary.ca
Ng
Jeffrey
J
Lueng
Alan
A
Khajah
Maitham
M
Parhar
Ken
K
Li
Yan
Y
Lam
Victor
V
Potentier
Mireille S
MS
Ng
Kelvin
K
Bawa
Misha
M
McCafferty
Donna-Marie
DM
Rioux
Kevin P
KP
Ghosh
Subrata
S
Xavier
Ramnik J
RJ
Colgan
Sean P
SP
Tschopp
Jurg
J
Muruve
Daniel
D
MacDonald
Justin A
JA
Beck
Paul L
PL
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002352:Carrier Proteins / Q000502:physiology*; D002633:Chemotaxis / Q000502:physiology; D003092:Colitis / Q000503:physiopathology*; D004195:Disease Models, Animal; D005663:Furans; D006706:Homeostasis / Q000502:physiology*; D007113:Immunity, Innate / Q000502:physiology; D058847:Inflammasomes / Q000502:physiology*; D016753:Interleukin-10 / Q000502:physiology; D053583:Interleukin-1beta / Q000502:physiology; D007422:Intestines / Q000502:physiology*; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D013876:Thiophenes; D016212:Transforming Growth Factor beta / Q000502:physiology
C516387:3,4-bis-(2,4,5-trimethyl-thiophen-3-yl)furan-2,5-dione; D002352:Carrier Proteins; D005663:Furans; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D013876:Thiophenes; D016212:Transforming Growth Factor beta; D016753:Interleukin-10