Endogenous Toll-Like Receptor 9 Regulates AKI by Promoting Regulatory T Cell Recruitment

Abstract

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.