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.
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.
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.
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. (Inflamm Bowel Dis 2011)
1 Gastrointestinal Research Group, University of Calgary, Calgary, AB, Canada
2 Inflammation Research Network, University of Calgary, Calgary, AB, Canada
3 Immunology Research Group, University of Calgary, Calgary, AB, Canada
4 Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Broad Institute of MIT, Boston, Massachusetts, USA
5 Mucosal Inflammation Program, Division of Gastroenterology, University of Colorado Health Sciences Center, Denver, Colorado, USA
6 Biochemistry, University of Lausanne, Dorigny, Switzerland
*Reprints: Gastrointestinal Research Group, University of Calgary, Calgary, AB, T2N 4N1 Canada
Received 3 August 2010; Accepted 4 August 2010
Published online 24 September 2010 in Wiley Online Library (wileyonlinelibrary.com).
Grant sponsor: CAG/CIHR and AHFMR fellowships; Grant sponsor: CRC and AHFMR Senior Scholar award; Grant sponsor: NIH grants; Grant Numbers: DK50189, DE13499, HL60569; Grant sponsor: CCFA; Grant sponsor: AHFMR Clinical Investigator\.