IL-10 from dendritic cells but not from T regulatory cells protects against cisplatin-induced nephrotoxicity.

Wei Wei Wang,W Brian Reeves,William E Friedrichs,Madhusudhan Budatha,Yamei Wang,Raghu Tadagavadi,Kang Li,Masaki Mogi

doi:10.1371/journal.pone.0238816

Abstract

Interleukin-10 (IL-10), a cytokine with anti-inflammatory effects, is produced by renal parenchymal cells and bone marrow derived cells. Both endogenous and exogenous IL-10 are protective in cisplatin-induced acute kidney injury. However, the source of endogenous IL-10 in cisplatin-induced nephrotoxicity is not clear. Bone marrow chimera experiments in IL10-KO mice indicated that bone marrow derived cells were the primary source of IL-10 in cisplatin nephrotoxicity. Cell specific deletion of IL-10 in T regulatory cells and dendritic cells was accomplished using Foxp3 and CD11c driven cre recombination in IL10flox/flox mice, respectively. Upon treatment with cisplatin, both the IL10flox/flox and the Foxp3YFP-Cre x IL10flox/flox mice developed similar degrees of kidney injury. However, mice with the dendritic cell deletion of IL-10 showed more severe structural and functional changes in the kidney compared to the IL10flox/flox mice. These results indicate that IL-10 from dendritic cells but not from T regulatory cells offers significant endogenous protection against cisplatin induced nephrotoxicity.

Highlights

Cisplatin is an effective chemotherapeutic agent used for treatment of various solid tumors
To investigate the source of IL-10 which mediates protection in cisplatin toxicity, we performed bone marrow transplantation to create three sets of chimeric mice; WT to WT; WT- to KO; and KO to WT and tested the differential role of bone marrow cell-derived versus parenchyma-derived IL-10 in cisplatin induced nephrotoxicity
Since the chimera results indicated that bone marrow derived cells were important sources of IL-10 during cisplatin nephrotoxicity, we explored the role of Treg cells by producing a Treg specific IL-10 knockout

Summary

Introduction

Cisplatin is an effective chemotherapeutic agent used for treatment of various solid tumors. Acute kidney injury is a major, and sometimes limiting, toxicity of cisplatin [1]. Various mediators of inflammation including chemokines, cytokines, TLRs and damage associated molecular patterns produced by renal parenchymal cells in response to cisplatin-induced injury [1,2,3,4,5,6,7]. These proinflammatory mediators recruit and activate leukocytes from the circulation and further aggravate kidney injury. In addition to proinflammatory molecules, anti-inflammatory pathways are activated in response to injury which inhibit ongoing cell injury and/or facilitate repair after the initial tubular injury [8,9,10] Previous reports suggest that some cytokines such as IL-4, IL-10, IL-3 and TGFβ may protect against tissue

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Results

Conclusion