title: 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.
authors: INSERM U773, Centre de Recherche Biomédicale Bichat Beaujon, Université Paris 7-Denis Diderot, Paris, France.
authors: Emilie
authors: E
authors: Tourneur
authors: Sanae
authors: S
authors: Ben Mkaddem
authors: Cécilia
authors: C
authors: Chassin
authors: Marcelle
authors: M
authors: Bens
authors: Jean-Michel
authors: JM
authors: Goujon
authors: Nicolas
authors: N
authors: Charles
authors: Christophe
authors: C
authors: Pellefigues
authors: Meryem
authors: M
authors: Aloulou
authors: Alexandre
authors: A
authors: Hertig
authors: Renato C
authors: RC
authors: Monteiro
authors: Stephen E
authors: SE
authors: Girardin
authors: Dana J
authors: DJ
authors: Philpott
authors: Eric
authors: E
authors: Rondeau
authors: Carole
authors: C
authors: Elbim
authors: Catherine
authors: C
authors: Werts
authors: Alain
authors: A
authors: Vandewalle
mesh_terms: D000208:Acute Disease; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D018925:Chemokines / Q000378:metabolism*; D016572:Cyclosporine / Q000009:adverse effects*; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D020868:Gene Silencing; D006801:Humans; D007113:Immunity, Innate; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016030:Kidney Transplantation / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein / Q000378:metabolism*; D009924:Organ Culture Techniques; D010587:Phagocytosis / Q000187:drug effects; D011704:Pyelonephritis / Q000139:chemically induced*
chemical_list: D018925:Chemokines; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein; D016572:Cyclosporine
references: Drugs. 1996 Feb;51(2):278-98
references: 8808168
references: Clin Infect Dis. 2001 Jul 1;33 Suppl 1:S5-8
references: 11389515
references: EMBO Mol Med. 2012 Apr;4(4):269-82
references: 22311511
references: Infect Immun. 2004 Mar;72(3):1487-95
references: 14977954
references: Gastroenterology. 2010 Apr;138(4):1546-56, 1556.e1-5
references: 20026116
references: J Immunol. 2007 Oct 1;179(7):4598-607
references: 17878357
references: Trends Immunol. 2009 Oct;30(10):475-87
references: 19781994
references: J Exp Med. 2006 Jan 23;203(1):203-13
references: 16418393
references: Nat Clin Pract Nephrol. 2008 May;4(5):252-64
references: 18334970
references: Genes Dev. 2003 Sep 15;17(18):2205-32
references: 12975316
references: J Biol Chem. 2003 Oct 24;278(43):41702-8
references: 12871942
references: Science. 2004 Mar 5;303(5663):1522-6
references: 15001781
references: Nat Immunol. 2003 Jul;4(7):702-7
references: 12796777
references: Infect Dis Clin North Am. 2010 Jun;24(2):273-83
references: 20466270
references: J Immunol. 2006 Oct 1;177(7):4773-84
references: 16982918
references: J Am Soc Nephrol. 2011 Aug;22(8):1435-41
references: 21757770
references: J Exp Med. 2007 Nov 26;204(12):2837-52
references: 17967904
references: Antimicrob Agents Chemother. 1994 Dec;38(12):2883-8
references: 7695277
references: Nature. 2002 Mar 14;416(6877):194-9
references: 11894098
references: J Immunol. 1999 Mar 1;162(5):3037-44
references: 10072556
references: J Cell Sci. 2007 Jul 15;120(Pt 14):2328-37
references: 17606988
references: J Antibiot (Tokyo). 1983 Aug;36(8):1059-66
references: 6630057
references: Nature. 2001 May 31;411(6837):603-6
references: 11385577
references: Cell. 2010 Mar 19;140(6):805-20
references: 20303872
references: J Immunol. 2011 Apr 15;186(8):4872-80
references: 21411735
references: Innate Immun. 2009 Apr;15(2):109-20
references: 19318421
references: J Immunol. 2001 Jan 15;166(2):1148-55
references: 11145696
references: Eur J Immunol. 2007 Sep;37(9):2499-508
references: 17705131
references: PLoS Pathog. 2007 Aug 24;3(8):e118
references: 17722978
references: Transpl Int. 2000;13(2):114-21
references: 10836647
references: Nat Med. 2004 Mar;10(3):305-9
references: 14770176
references: Q J Med. 1994 May;87(5):311-4
references: 7938411
references: Kidney Int. 2007 Nov;72(9):1051-6
references: 17653134
references: Brain Res. 2011 Jun 23;1397:55-65
references: 21435337
references: Eur J Immunol. 2005 Aug;35(8):2459-70
references: 16021602
references: Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14896-901
references: 21856952
references: Nature. 1994 Jun 9;369(6480):497-502
references: 8202141
references: Infect Immun. 2000 May;68(5):2566-72
references: 10768945
references: J Infect Dis. 1999 Oct;180(4):1220-9
references: 10479151
references: Transplantation. 2001 Feb 27;71(4):575-7
references: 11258440
references: J Am Soc Nephrol. 1990 Aug;1(2):162-79
references: 2104260
references: Nature. 2001 May 31;411(6837):599-603
references: 11385576
references: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4203-8
references: 12655047
references: J Exp Med. 2010 May 10;207(5):923-31
references: 20421389
references: Nephrol Dial Transplant. 2003 May;18(5):983-9
references: 12686675
references: PLoS Pathog. 2010 Aug 12;6(8):e1001042
references: 20811584
references: Nephrology (Carlton). 2012 May;17(4):364-71
references: 22320441
references: Curr Opin Urol. 2002 Mar;12(2):125-30
references: 11859258
references: Nat Med. 2010 Feb;16(2):228-31
references: 20081863
references: J Immunol. 2005 Mar 15;174(6):3633-42
references: 15749901
references: Am J Kidney Dis. 2004 Aug;44(2):353-62
references: 15264195
references: Cell Signal. 2011 Nov;23(11):1785-93
references: 21726630
references: Eur J Clin Invest. 2008 Oct;38 Suppl 2:21-8
references: 18826478
references: Kidney Int. 2005 Dec;68(6):2582-7
references: 16316333
references: Nephrol Dial Transplant. 2005 Oct;20(10):2226-30
references: 16030032
references: Nat Med. 2007 Nov;13(11):1368-74
references: 17934470
references: Nat Rev Microbiol. 2012 Mar 16;10(4):243-54
references: 22421877
references: Science. 1999 Sep 24;285(5436):2129-33
references: 10497131
references: Cell Microbiol. 2011 Aug;13(8):1107-13
references: 21615666
references: Nat Rev Microbiol. 2011 Dec 12;10(2):112-22
references: 22158429
references: J Am Soc Nephrol. 2007 Oct;18(10):2628-35
references: 17804672
references: EMBO Rep. 2001 Aug;2(8):736-42
references: 11463746
references: Infect Immun. 1997 Aug;65(8):3451-6
references: 9234811
references: Am J Transplant. 2007 Apr;7(4):899-907
references: 17286620
references: J Biol Chem. 1996 May 3;271(18):10884-91
references: 8631904
references: Kidney Int. 2011 Jul;80(2):139-45
references: 21613986
references: J Immunol. 2010 Mar 1;184(5):2297-304
references: 20124104