Endogenous toll-like receptor 9 regulates AKI by promoting regulatory T cell recruitment

Maliha Alikhan, Shaun Andrew Summers, Poh Yi Gan, Amy Chan, Mary Khouri, Joshua Ooi, Joanna Ghali, Dragana Odobasic, Michael John Hickey, Arthur Richard Kitching, Stephen Roger Holdsworth

Research output: Contribution to journalArticleResearchpeer-review

19 Citations (Scopus)

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 Foxp3DTR 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.
Original languageEnglish
Pages (from-to)706 - 714
Number of pages9
JournalJournal of the American Society of Nephrology
Volume27
Issue number3
DOIs
Publication statusPublished - 2016

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