TLR2 and TLR4 expression after kidney ischemia and reperfusion injury in mice treated with FTY720

Abstract

Ischemia and reperfusion injury (IR) is an antigen independent inflammatory process that causes tissue damage. After IR, kidneys up-regulate leukocyte adhesion molecules and toll-like receptors (TLRs). Moreover, injured kidneys can also secrete factors (i.e. heat shock protein) which bind to TLRs and trigger intracellular events culminating with the increase in the gene expression of inflammatory cytokines. FTY720 is an immunomodulatory compound and protects at least in part kidneys submitted to IR. The mechanisms associated with FTY720's beneficial effects on kidneys after IR remain elusive. We investigated whether FTY720 administration in mice submitted to kidney IR is associated with modulation of TLR2 and TLR4 expression. C57BL/6 mice submitted to 30min of renal pedicles clamp were evaluated for serum parameters (creatinine, urea and nitric oxide), kidney histology, spleen and kidney infiltrating cells expression of TLR2 and TLR4, resident kidney cells expression of TLR2 and TLR4 and IL-6 protein expression in kidney. FTY720-treated mice presented decrease in serum creatinine, urea and nitric oxide, diminished expression of TLR2 and TLR4 both in spleen and kidney infiltrating cells, and reduced kidney IL-6 protein expression in comparison with IR non-treated mice. However, acute tubular necrosis was present both in IR non-treated and IR+FTY720-treated groups. Also, FTY720 did not prevent TLR2 and TLR4 expression in kidney resident cells. In conclusion, FTY720 can promote kidney function recovery after IR by reducing the inflammatory process. Further studies are needed in order to establish whether TLR2 and TLR4 down regulation should be therapeutically addressed as protective targets of renal function and structure after IR.

Upregulation of TLR4 mRNA Expression Levels in Broiler Chickens Under Acute Heat Stress

“…In the present study, the TLR4 mRNA expression levels in the kidneys were markedly increased in the HS5 and HS10 groups compared with the control group, demonstrating that the kidneys were seriously impacted by AHS. In addition, previous research has shown a marked increase in TLR2 and TLR4 expression in renal tubular cells and in renal infiltrating cells caused by ischemia and reperfusion injury compared with control group (Kim et al, 2005;Pedregosa et al, 2011). Cunningham et al (2004) reported that TLR4 expression in the kidneys was critical in mediating LPS-induced acute kidney failure via proinflammatory cytokine release and subsequent kidney damage.…”

“…This means that down regulated TLR4 and TLR7 mRNA expression levels in the spleen are beneficial to its immune function. On the other hand, Pedregosa et al (2011) indicated that ischemia and reperfusion injury caused a significant increase of TLR2 and TLR4 expression levels in spleen cells. In the present study, the TLR4 mRNA expression levels in the spleen were consistent with those observed in the small intestine, which were significantly reduced in the HS2 group and markedly elevated in the HS10 group.…”

FTY720 induces apoptosis in B16F10-NEX2 murine melanoma cells, limits metastatic development in vivo, and modulates the immune system

“…The compound is a substrate for sphingosine kinases (SphK1 and SphK2); its phosphorylated form, FTY720-P, acts as an agonist of sphingosine 1-phosphate (S1P) receptors (S1P1, S1P3, S1P4, S1P5), binding to them with high affinity at sub-nano-molar concentrations (1). Several groups have shown that FTY720 increases allograft survival (2,3), promotes earlier recovery from ischemia and reperfusion injury (4), and attenuates autoimmune diseases (5,6). The mechanisms underlying the effects of FTY720 were first described as the sequestration of lymphocytes in the thymus and secondary lymphoid organs, thus preventing their migration to inflammatory sites.…”

Toll-Like Receptors 2 and 4 in Pigs' Kidneys Early After Autotransplantation Procedure

“…In the early postoperative period, mRNA for TLR2 was dominant, then decreasing by the 30th day with simultaneous increase in expression for TLR4 and MyD88. Very quick activation of TLR2 and related intensified inflammatory reaction might be the result of significant extent of ischemia-reperfusion injury, which is confirmed by further observations [8]. Undoubtedly, TLR2 function blocking in the early reperfusion period inhibits production of inflammatory mediators and is beneficial for maintaining organ functioning [9].…”