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 kidney grafts to APN.
Patients who have received a kidney graft are treated with immunosuppressive drugs, such as the cyclosporine A (CsA). Transplanted patients under CsA are prone to bacterial infections. In this study, we used an experimental mouse model of kidney infection with Escherichia coli (E. coli) bacteria to study the effect of CsA. We show that CsA treatment of mice reduced their renal defense against E. coli. We found that CsA, in addition to its inhibitory action on the TLR4-mediated production of chemoattractant chemokines, also inhibited the expression of nucleotide-binding oligomerization domain 1 (Nod1), an intracellular receptor involved in the innate immune response against bacteria, in phagocytic cells. CsA acts by inhibiting the functions of the transcription factor NFAT. We show that NFAT is required for the proper expression of Nod1. Since Nod1 has already been reported to be involved in the phagocytic functions of polymorphonuclear neutrophils, we looked for and found a severe defect in neutrophil bacterial killing associated with reduced expression of Nod1 in both mice and patients treated by CsA. Interestingly, when mice treated with CsA are given synthetic molecules known to bind Nod1, this permitted the restoration of the Nod1 expression and renal defenses. This paper describes a novel mechanism which may explain, at least in part, why transplant patients receiving CsA have increased susceptibility to bacterial infection, and also provides a potential therapeutic strategy to restore renal antibacterial defenses.