Protective and aggravating effects of Nlrp3 inflammasome activation in IBD models: influence of genetic and environmental factors.
BACKGROUND
Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation due to dysregulation of the mucosal immune system. The cytokines IL-1β and IL-18 appear early in intestinal inflammation and their pro-forms are processed via the caspase-1-activating multiprotein complex, the Nlrp3 inflammasome. Previously, we reported that the uptake of dextran sodium sulfate (DSS) by macrophages activates the Nlrp3 inflammasome and that Nlrp3(-/-) mice are protected in the acute DSS colitis model. Of note, other groups have reported opposing effects in regards to DSS susceptibility in Nlrp3(-/-) mice. Recently, mice lacking inflammasomes were found to develop a distinct intestinal microflora.


METHODS
To reconcile the contradicting observations, we investigated the role of Nlrp3 deficiency in two different IBD models: acute DSS colitis and TNBS (2,4,6-trinitrobenzene sulfonic acid)-induced colitis. In addition, we investigated the impact of the intestinal flora on disease severity by performing cohousing experiments of wild-type and Nlrp3(-/-) mice, as well as by antibiotic treatment.


RESULTS
Nlrp3(-/-) mice treated with either DSS or TNBS exhibited attenuated colitis and lower mortality. This protective effect correlated with an increased frequency of CD103+ lamina propria dendritic cells expressing a tolerogenic phenotype in Nlrp3(-/-) mice in steady state conditions. Interestingly, after cohousing, Nlrp3(-/-) mice were as susceptible as wild-type mice, indicating that transmission of endogenous bacterial flora between the two mouse strains might increase susceptibility of Nlrp3(-/-) mice towards DSS-induced colitis. Accordingly, treatment with antibiotics almost completely prevented colitis in the DSS model.


CONCLUSIONS
The composition of the intestinal microflora significantly influences disease severity in IBD models comparing wild-type and Nlrp3(-/-) mice. This observation may - at least in part - explain contradictory results concerning the role of the inflammasome in different labs. Further studies are required to define the role of the Nlrp3 inflammasome in noninflamed mucosa under steady state conditions and in IBD.
Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, München, Germany.
Christian
C
Bauer
Peter
P
Duewell
Hans-Anton
HA
Lehr
Stefan
S
Endres
Max
M
Schnurr
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D002352:Carrier Proteins / Q000378:metabolism*; D003092:Colitis / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D004777:Environment; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D058847:Inflammasomes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D007422:Intestines / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D054892:Metagenome; D051379:Mice; D009092:Mucous Membrane / Q000276:immunology / Q000473:pathology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010641:Phenotype; D020011:Protective Agents / Q000378:metabolism*; D014302:Trinitrobenzenesulfonic Acid
D000900:Anti-Bacterial Agents; D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D020011:Protective Agents; D014302:Trinitrobenzenesulfonic Acid