Cyclosporine A Impairs Nucleotide Binding Oligomerization Domain (Nod1)-Mediated Innate Antibacterial Renal Defenses in Mice and Human Transplant Recipients

Abstract

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.

The Calcineurin-NFAT Axis Controls Allograft Immunity in Myeloid-Derived Suppressor Cells through Reprogramming T Cell Differentiation

“…The susceptibility to fungal infection caused by CsA was also shown to be the consequence of an innate immune pathway regulating antifungal resistance in neutrophils (47). CsA can also impair nucleotide binding oligomerization domain 1 (Nod1)-mediated innate antibacterial renal defenses in mice and human transplant recipients, and these results confirmed that inhibition of Nod1-mediated innate immune response together with the decrease in Toll-like receptor 4 (TLR4)-mediated production of chemoattractant chemokines caused by CsA may contribute to sensitizing kidney grafts to acute pyelonephritis (48). However, the immune regulatory effect and important role in transplant immunology of calcineurin inhibitors is highly complex.…”

“…Although NFATs have been extensively studied in the context of T cells, relatively few studies have examined their function in myeloid lineages. However, several recent studies about calcineurin signaling in innate immune effects have showed their NFAT-dependent regulatory effects (45)(46)(47)(48). In the present study, we demonstrate the intrinsic regulatory effects of MDSCs in prolonging allograft survival and show a previously unknown feature of MDSC function in immunohomeostasis, i.e., the reprogramming of T cell differentiation from T H 1 to T H 2 and CD8 ϩ T cell differentiation, which represents a novel mechanism of calcineurin amelioration of transplant immunological rejection by targeting the NFAT signaling pathway.…”

Calcineurin Orchestrates Lateral Transfer of Aspergillus fumigatus during Macrophage Cell Death

“…This pathway is crucial for activation of inflammatory responses to Af and for recruitment of fungicidal neutrophils to the site of infection. Calcineurin-NFAT signaling has also been shown to be critical for the innate immune response to Candida albicans and Escherichia coli through endocytic mechanisms convergent on phospholipase C-g-dependent calcium flux (16,17). These observations underscore the importance of calcineurin-NFAT signaling for myeloid immunity, and they reveal a novel relationship between innate sensing and calcineurin-NFAT signaling in the lung that requires further clinical definition.…”

Cyclosporine A Induces MicroRNAs Controlling Innate Immunity during Renal Bacterial Infection

“…Since we previously showed that CsA impairs Nod1 expression in renal tubular cells infected with UPEC [16], we checked that Let-7i had no effect on Nod1 expression (online suppl. Fig.…”

“…Interestingly, CsA was also shown to impair cytokine-induced matrix-metalloproteinase-9 associated with an inhibition of the IL-1β-induced activation of the transcription factor NF-κB and mitogen-activated protein (MAP) kinase c-Jun N-terminal kinase (JNK) in rat mesangial cells [15]. Moreover, we previously showed that CsA impairs nucleotide binding oligomerisation domain (Nod1)-mediated innate antibacterial renal defenses in mice and human transplant recipients [16,17]. These findings raised the possibility that CsA can impair the activation of MCD cells caused by LPS and UPEC, and thereby favour the intrarenal colonisation of UPEC.…”