Contributors: Centre de recherche biomédicale Bichat-Beaujon (CRB3); Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM); Immunopathologie rénale, récepteurs et inflammation; Université de Poitiers = University of Poitiers (UP); Centre hospitalier universitaire de Poitiers = Poitiers University Hospital (CHU de Poitiers La Milétrie ); Remodelage et Reparation du Tissu Renal (UMR S702); Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM); CHU Tenon AP-HP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU); University of Toronto; Immunité et Infection; Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR113-Institut National de la Santé et de la Recherche Médicale (INSERM); CHU Pitié-Salpêtrière AP-HP; Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall (BGPB); Institut Pasteur Paris (IP); AV was in receipt of a Contrat Hospitalier de Recherche Translationnelle (CHRP) INSERM-APHP, 2010. CW salary was funded in part by an ERC grant (PGNfromSHAPEtoVIR 202283, to Ivo Boneca, Institut Pasteur, Paris, France). ET was in receipt of a French Research Ministry thesis grant, and a “Bourse de fin de thèse” FRM grant. The work has been supported by INSERM, and in part by grants from the Agence de la Biomédecine 2007, 2009 (to AV), and from the French National Agency under reference ANR-08-MIE-030 (to AV, ER, and CW). CC is in receipt of a 2011 ATIP-AVENIR grant.; ANR-08-MIEN-0030,TOLLNODPYELO,Pyélonéphrites dues aux bactéries uropathogènes : régulation de la réponse immunitaire innée par les récepteurs Toll-like et Nod(2008); European Project: 202283,EC:FP7:ERC,ERC-2007-StG,PGNFROMSHAPETOVIR(2008)
نبذة مختصرة : International audience ; Acute pyelonephritis (APN), which is mainly caused by uropathogenic Escherichia coli (UPEC), is the most common bacterial complication in renal transplant recipients receiving immunosuppressive treatment. However, it remains unclear how immunosuppressive drugs, such as the calcineurin inhibitor cyclosporine A (CsA), decrease renal resistance to UPEC. Here, we investigated the effects of CsA in host defense against UPEC in an experimental model of APN. We show that CsA-treated mice exhibit impaired production of the chemoattractant chemokines CXCL2 and CXCL1, decreased intrarenal recruitment of neutrophils, and greater susceptibility to UPEC than vehicle-treated mice. Strikingly, renal expression of Toll-like receptor 4 (Tlr4) and nucleotide-binding oligomerization domain 1 (Nod1), neutrophil migration capacity, and phagocytic killing of E. coli were significantly reduced in CsA-treated mice. CsA inhibited lipopolysaccharide (LPS)-induced, Tlr4-mediated production of CXCL2 by epithelial collecting duct cells. In addition, CsA markedly inhibited Nod1 expression in neutrophils, macrophages, and renal dendritic cells. CsA, acting through inhibition of the nuclear factor of activated T-cells (NFATs), also markedly downregulated Nod1 in neutrophils and macrophages. Silencing the NFATc1 isoform mRNA, similar to CsA, downregulated Nod1 expression in macrophages, and administration of the 11R-VIVIT peptide inhibitor of NFATs to mice also reduced neutrophil bacterial phagocytosis and renal resistance to UPEC. Conversely, synthetic Nod1 stimulating agonists given to CsA-treated mice significantly increased renal resistance to UPEC. Renal transplant recipients receiving CsA exhibited similar decrease in NOD1 expression and neutrophil phagocytosis of E. coli. The findings suggest that such mechanism of NFATc1-dependent inhibition of Nod1-mediated innate immune response together with the decrease in Tlr4-mediated production of chemoattractant chemokines caused by CsA may contribute to sensitizing ...
Processing Request
No Comments.