Endogenous Toll-Like Receptor 9 Regulates AKI by Promoting Regulatory T Cell Recruitment.
Toll-like receptor 9 (TLR9) enhances proinflammatory responses, but whether it can act in a regulatory capacity remains to be established. In experimental murine AKI induced by cisplatin, Tlr9(-/-) mice developed enhanced renal injury and exhibited fewer intrarenal regulatory T cells (Tregs) compared with genetically intact mice. A series of reconstitution and depletion studies defined a role for TLR9 in maintaining Treg-mediated homeostasis in cisplatin-induced AKI. When Rag1(-/-) mice were reconstituted with nonregulatory CD25(-) splenocytes from wild-type (WT) or Tlr9(-/-) mice, AKI was similarly enhanced. However, when Rag1(-/-) mice were reconstituted with CD4(+)CD25(+) regulatory cells, WT CD4(+)CD25(+) cells were more renoprotective and localized to the kidney more efficiently than Tlr9(-/-) CD4(+)CD25(+) cells. In Treg-depleted Foxp3(DTR) mice, reconstitution with naive WT CD4(+)CD25(+) cells resulted in less severe AKI than did reconstitution with Tlr9(-/-) Tregs. Tlr9(-/-) mice were not deficient in CD4(+)CD25(+) cells, and WT and TLR9-deficient Tregs had similar suppressive function ex vivo. However, expression of adhesion molecules important in Treg trafficking was reduced on peripheral CD4(+)CD25(+) cells from Tlr9(-/-) mice. In conclusion, we identified a pathway by which TLR9 promotes renal Treg accumulation in AKI.
['Alikhan|Maliha A|MA|', 'Summers|Shaun A|SA|', 'Gan|Poh Y|PY|', 'Chan|Amy J|AJ|', 'Khouri|Mary B|MB|', 'Ooi|Joshua D|JD|', 'Ghali|Joanna R|JR|', 'Odobasic|Dragana|D|', 'Hickey|Michael J|MJ|', 'Kitching|A Richard|AR|', 'Holdsworth|Stephen R|SR|']
D058186:Acute Kidney Injury D000818:Animals D040881:CD11a Antigen D002945:Cisplatin D018398:Homeodomain Proteins D018960:Hyaluronan Receptors D039441:Integrin alpha4 D008213:Lymphocyte Activation D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D050378:T-Lymphocytes, Regulatory D051217:Toll-Like Receptor 9
Toll-like receptor 9 Regulatory T cells acute renal failure cisplatin nephrotoxicity