The regenerating family member 3 β instigates IL-17A-mediated neutrophil recruitment downstream of NOD1/2 signalling for controlling colonisation resistance independently of microbiota community structure.
OBJECTIVE
Loss of the Crohn's disease predisposing NOD2 gene results in an intestinal microenvironment conducive for colonisation by attaching-and-effacing enteropathogens. However, it remains elusive whether it relies on the intracellular recruitment of the serine-threonine kinase RIPK2 by NOD2, a step that is required for its activation of the transcription factor NF-κB.


DESIGN
Colonisation resistance was evaluated in wild type and mutant mice, as well as in ex-germ-free (ex-GF) mice which were colonised either with faeces from Ripk2-deficient mice or with bacteria with similar preferences for carbohydrates to those acquired by the pathogen. The severity of the mucosal pathology was quantified at several time points postinfection by using a previously established scoring. The community resilience in response to infection was evaluated by 16S ribosomal RNA gene sequence analysis. The control of pathogen virulence was evaluated by monitoring the secretion of Citrobacter-specific antibody response in the faeces.


RESULTS
Primary infection was similarly outcompeted in ex-GF Ripk2-deficient and control mice, demonstrating that the susceptibility to infection resulting from RIPK2 deficiency cannot be solely attributed to specific microbiota community structures. In contrast, delayed clearance of Citrobacter rodentium and exacerbated histopathology were preceded by a weakened propensity of intestinal macrophages to afford innate lymphoid cell activation. This tissue protection unexpectedly required the regenerating family member 3β by instigating interleukin (IL) 17A-mediated neutrophil recruitment to the intestine and subsequent phosphorylation of signal transducer and activator of transcription 3.


CONCLUSIONS
These results unveil a previously unrecognised mechanism that efficiently protects from colonisation by diarrhoeagenic bacteria early in infection.
['Waldschmitt|Nadine|N|', 'Kitamoto|Sho|S|', 'Secher|Thomas|T|', 'Zacharioudaki|Vassiliki|V|', 'Boulard|Olivier|O|', 'Floquet|Emilie|E|', 'Delacre|Myriam|M|', 'Lamas|Bruno|B|', 'Pham|Hang-Phuong|HP|', 'Six|Adrien|A|', 'Richard|Mathias L|ML|', 'Dagorn|Jean-Charles|JC|', 'Eberl|Gérard|G|', 'Langella|Philippe|P|', 'Chatel|Jean-Marc|JM|', 'Ryffel|Bernhard|B|', 'Iovanna|Juan Lucio|JL|', 'Poulin|Lionel F|LF|', 'Sokol|Harry|H|', 'Kamada|Nobuhiko|N|', 'Chamaillard|Mathias|M|']
D000818:Animals D053468:CARD Signaling Adaptor Proteins D044082:Citrobacter rodentium D003424:Crohn Disease D004195:Disease Models, Animal D004756:Enterobacteriaceae Infections D020381:Interleukin-17 D007413:Intestinal Mucosa D051379:Mice D020556:Neutrophil Infiltration D053473:Nod2 Signaling Adaptor Protein D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 D053422:Receptor-Interacting Protein Serine-Threonine Kinases D015398:Signal Transduction
Macrophages Interleukins Antibacterial Peptide Barrier Function Colonic Microflora