NLRP3 inflammasome plays a key role in the regulation of intestinal homeostasis

Autor: Subrata Ghosh, Yan Li, Victor Lam, Simon A. Hirota, Ramnik J. Xavier, Kelvin Ng, Daniel A. Muruve, Paul L. Beck, Mireille S. Potentier, Sean P. Colgan, Jeffrey Ng, Ken Kuljit S. Parhar, Donna-Marie McCafferty, Kevin P. Rioux, Jürg Tschopp, Misha Bawa, Justin A. MacDonald, Maitham A. Khajah, Alan Lueng
Rok vydání: 2011
Předmět:
Inflammasomes
medicine.medical_treatment
Interleukin-1beta
Apoptosis
Thiophenes
Article
Microbiology
Mice
chemistry.chemical_compound
Transforming Growth Factor beta
NLR Family
Pyrin Domain-Containing 3 Protein
medicine
Animals
Homeostasis
Immunology and Allergy
Furans
NLRP6
Innate immune system
integumentary system
biology
Chemotaxis
Gastroenterology
Inflammasome
Transforming growth factor beta
Colitis
Immunity
Innate
Interleukin-10
Respiratory burst
Intestines
Disease Models
Animal
Interleukin 10
Cytokine
chemistry
Immunology
biology.protein
Carrier Proteins
Muramyl dipeptide
Apoptosis/physiology
Carrier Proteins/physiology
Chemotaxis/physiology
Colitis/physiopathology
Homeostasis/physiology
Immunity
Innate/physiology
Inflammasomes/physiology
Interleukin-10/physiology
Interleukin-1beta/physiology
Intestines/physiology
Transforming Growth Factor beta/physiology
medicine.drug
Zdroj: Inflammatory Bowel Diseases, vol. 17, no. 6, pp. 1359-1372
ISSN: 1078-0998
DOI: 10.1002/ibd.21478
Popis: 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. (Inflamm Bowel Dis 2010).
Databáze: OpenAIRE
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