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TLR2 is critical for induction of REG3β expression and intestinal clearance of Yersinia pseudotuberculosis.
  1. Rodrigue Dessein
  1. Inserm, France
    1. Meritxell Gironella
    1. CIBEREHD, Spain
      1. Cécile Vignal
      1. Inserm, France
        1. Laurent Peyrin-Biroulet
        1. Inserm, France
          1. Harry Sokol
          1. INRA, France
            1. Thomas Secher
            1. CNRS, France
              1. sandra Lacas-Gervais
              1. CNRS, France
                1. Jean-Jacques Gratadoux
                1. INRA, France
                  1. Frank Lafont
                  1. CNRS, France
                    1. Jean-Charles Dagorn
                    1. CNRS, France
                      1. Bernhard Ryffel
                      1. CNRS, France
                        1. Shizuo Akira
                        1. Osaka University, France
                          1. Philippe Langella
                          1. INRA, France
                            1. Gabriel Nùñez
                            1. University of Michigan, United States
                              1. Jean-Claude Sirard
                              1. Inserm, France
                                1. Juan Iovanna
                                1. Inserm, France
                                  1. Michel Simonet
                                  1. Inserm, France
                                    1. Mathias Chamaillard (mathias.chamaillard{at}ibl.fr)
                                    1. Inserm, France

                                      Abstract

                                      Objective: Yersinia pseudotuberculosis causes ileitis and mesenteric lymphadenitis by mainly invading the Peyer’s patches (PPs) that are positioned in the terminal ileum. Whereas Toll-like-receptor 2 (TLR2) controls mucosal inflammation by detecting certain microbiota-derived signals, its exact role in protecting PPs against bacterial invasion has not been defined.

                                      Design: Wild-type, Tlr2-, Nod2- and MyD88-deficient animals were challenged by Y. pseudotuberculosis via oral or systemic route. The role of microbiota in conditioning PPs against Yersinia through TLR2 was assessed by delivering ad libitum exogenous TLR2 agonists in drinking water to Germ-Free and streptomycin-treated animals. Bacterial eradication from PPs was measured by using a colony-forming unit assay. Expression of cryptdins and the c-type lectin Reg3β were quantified by quantitative RT-PCR.

                                      Results: Our data demonstrated that Tlr2-deficient mice failed to limit Yersinia dissemination from the PPs and succumbed to sepsis independently of NOD2. Recognition of both microbiota-derived and MyD88-mediated elicitors was found to be critically involved in gut protection against Yersinia-induced lethality, while TLR2 was dispensable to systemic Yersinia infection. Gene expression analyses revealed that optimal epithelial transcript level of the anti-infective Reg3β requires TLR2 activation. Consistently, Yersinia infection triggered TLR2-dependent Reg3β expression in PPs. Importantly, oral treatment with exogenous TLR2 agonists in Germ-Free animals was able to further enhance Yersinia-induced expression of Reg3β and to restore intestinal resistance to Yersinia. Lastly, genetic ablation of Reg3β resulted in impaired clearance of the bacterial load in PPs.

                                      Conclusions: TLR2/REG3β is thus an essential component in conditioning epithelial defense signaling pathways against bacterial invasion.

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