IMMUNOSUPPRESSIVE AGENTS INDUCE MICRORNAS CONTROLLING INNATE IMMUNITY DURING RENAL BACTERIAL INFECTIONS

Urinary tract infections (UTI) and pyelonephritis, mainly due to uropathogenic Escherichia coli(UPEC), is the most common bacterial infection observed in renal transplanted patients that may compromise renal graft function.  Cyclosporine A (CsA) is an immunosuppressant drug widely used in prevention after organ transplantation, which inhibits T-cell proliferation and activation.We already showed that renal collecting duct (RCD) cells are a preferential site of UPECs adhesion and initiation of Toll-like receptor 4 (TLR4)-mediated inflammatory response for host defense. Immunosuppressive therapy post-transplant increases the risk of bacterial infection and eventually subsequent graft failure, but the cellular mechanism by which they favor UTI remains elusive. The aim of the study was to determine the effects of CsA on cellular mechanisms involved in innate host defense against UPEC in RCD cells. The results show that TLR4 expression is downregulated by CsA on RCD, leading to a decrease of UPEC-induced cytokine production and an increase of bacterial proliferation in the kidney.  Results were confirmed in a mouse model of urinary tract infection. We also showed that the downregulation of TLR4 expression by CsA is dependent of the induction of a microRNA specifically targeting TLR4. The injection of an antagomiR to UPEC-infected mice treated with CsA reestablishes the production of cytokines by RCD and favors bacterial clearance. These findings could explain the greater sensitivity of patients to UTI after transplantation and highlight the possible use of microRNAs as therapeutic tool to prevent progressive alteration of the graft.