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

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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

Cite this

@article{84daa94bfb2149eb9b2db63cafb6839b,
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 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.",
author = "Maliha Alikhan and Summers, {Shaun Andrew} and Gan, {Poh Yi} and Amy Chan and Mary Khouri and Joshua Ooi and Joanna Ghali and Dragana Odobasic and Hickey, {Michael John} and Kitching, {Arthur Richard} and Holdsworth, {Stephen Roger}",
year = "2016",
doi = "10.1681/ASN.2014090927",
language = "English",
volume = "27",
pages = "706 -- 714",
journal = "Journal of the American Society of Nephrology",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "3",

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TY - JOUR

T1 - Endogenous toll-like receptor 9 regulates AKI by promoting regulatory T cell recruitment

AU - Alikhan, Maliha

AU - Summers, Shaun Andrew

AU - Gan, Poh Yi

AU - Chan, Amy

AU - Khouri, Mary

AU - Ooi, Joshua

AU - Ghali, Joanna

AU - Odobasic, Dragana

AU - Hickey, Michael John

AU - Kitching, Arthur Richard

AU - Holdsworth, Stephen Roger

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

UR - http://www.ncbi.nlm.nih.gov/pubmed/26116356

U2 - 10.1681/ASN.2014090927

DO - 10.1681/ASN.2014090927

M3 - Article

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SP - 706

EP - 714

JO - Journal of the American Society of Nephrology

JF - Journal of the American Society of Nephrology

SN - 1046-6673

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