title: 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.
authors.affiliation: Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia;
authors.forename: Maliha A
authors.initials: MA
authors.lastname: Alikhan
authors.affiliation: Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia; Department of Nephrology, Monash Health, Clayton, Victoria, Australia; and.
authors.forename: Shaun A
authors.initials: SA
authors.lastname: Summers
authors.affiliation: Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia;
authors.forename: Poh Y
authors.initials: PY
authors.lastname: Gan
authors.affiliation: Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia;
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Chan
authors.affiliation: Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia;
authors.forename: Mary B
authors.initials: MB
authors.lastname: Khouri
authors.affiliation: Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia;
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Ooi
authors.affiliation: Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia; Department of Nephrology, Monash Health, Clayton, Victoria, Australia; and.
authors.forename: Joanna R
authors.initials: JR
authors.lastname: Ghali
authors.affiliation: Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia;
authors.forename: Dragana
authors.initials: D
authors.lastname: Odobasic
authors.affiliation: Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia;
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hickey
authors.affiliation: Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia; Department of Nephrology, Monash Health, Clayton, Victoria, Australia; and Department of Pediatric Nephrology, Monash Health, Clayton, Victoria, Australia.
authors.forename: A Richard
authors.initials: AR
authors.lastname: Kitching
authors.affiliation: Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia; Department of Nephrology, Monash Health, Clayton, Victoria, Australia; and stephen.holdsworth@monash.edu.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Holdsworth
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism*; D000818:Animals; D040881:CD11a Antigen / Q000378:metabolism; D002945:Cisplatin; D018398:Homeodomain Proteins / Q000235:genetics; D018960:Hyaluronan Receptors / Q000378:metabolism; D039441:Integrin alpha4 / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D040881:CD11a Antigen; D018398:Homeodomain Proteins; D018960:Hyaluronan Receptors; D051217:Toll-Like Receptor 9; C064658:RAG-1 protein; D039441:Integrin alpha4; D002945:Cisplatin
keywords: Regulatory T cells; Toll-like receptor 9; acute renal failure; cisplatin nephrotoxicity