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Conventional DCs reduce liver ischemia/reperfusion injury in mice via IL-10 secretion
Zubin M. Bamboat, … , George Plitas, Ronald P. DeMatteo
Zubin M. Bamboat, … , George Plitas, Ronald P. DeMatteo
Published January 19, 2010
Citation Information: J Clin Invest. 2010;120(2):559-569. https://doi.org/10.1172/JCI40008.
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Research Article Immunology

Conventional DCs reduce liver ischemia/reperfusion injury in mice via IL-10 secretion

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Abstract

TLRs are recognized as promoters of tissue damage, even in the absence of pathogens. TLR binding to damage-associated molecular patterns (DAMPs) released by injured host cells unleashes an inflammatory cascade that amplifies tissue destruction. However, whether TLRs possess the reciprocal ability to curtail the extent of sterile inflammation is uncertain. Here, we investigated this possibility in mice by studying the role of conventional DCs (cDCs) in liver ischemia/reperfusion (I/R) injury, a model of sterile inflammation. Targeted depletion of mouse cDCs increased liver injury after I/R, as assessed by serum alanine aminotransferase and histologic analysis. In vitro, we identified hepatocyte DNA as an endogenous ligand to TLR9 that promoted cDCs to secrete IL-10. In vivo, cDC production of IL-10 required TLR9 and reduced liver injury. In addition, we found that inflammatory monocytes recruited to the liver via chemokine receptor 2 were downstream targets of cDC IL-10. IL-10 from cDCs reduced production of TNF, IL-6, and ROS by inflammatory monocytes. Our results implicate inflammatory monocytes as mediators of liver I/R injury and reveal that cDCs respond to DAMPS during sterile inflammation, providing the host with protection from progressive tissue damage.

Authors

Zubin M. Bamboat, Lee M. Ocuin, Vinod P. Balachandran, Hebroon Obaid, George Plitas, Ronald P. DeMatteo

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Figure 7

cDC IL-10 suppresses inflammatory monocyte function during I/R.

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cDC IL-10 suppresses inflammatory monocyte function during I/R.
Ischemic...
Ischemic liver CD45+ NPCs from CD11c-DTR mice treated with DT or PBS prior to 12 hours of I/R were cultured with Brefeldin A. (A) Intracellular IL-6 and TNF was determined 6 hours later. Numbers indicate the percentages within each gated region of cytokine staining in excess of isotype controls. More than 95% of the Ly6Chi cells depicted are CD11b+ (data not shown). The bar graph depicts inflammatory monocyte cytokine production as MFI above isotype pooled from 3 experiments. (B) IL-10 receptor expression was measured on inflammatory monocytes, neutrophils, and Kupffer cells from ischemic livers of PBS-treated CD11c-DTR mice 12 hours after I/R or sham procedure. MFI values above isotype controls are shown and pooled from 3 experiments. Recipient CD11c-DTR mice pretreated with DT were injected with WT or Il10–/– cDCs just prior to hepatic ischemia or sham procedure. (C) Twelve hours later, oxidative burst was measured (red line indicates sham treatment with WT cDCs; blue line indicates sham treatment with Il10–/– cDCs; shaded area indicates I/R treatment with WT cDCs; bold line indicates I/R treatment with Il10–/– cDCs). (D) Intracellular IL-6 and TNF production by inflammatory monocytes from liver CD45+ NPCs was measured and expressed as a percentage above isotype controls (black lines indicate isotype control; shaded area indicates sham treatment; bold lines indicate I/R treatment). The bar graphs in C and D depict data pooled from 3 experiments. (D) MFI values above isotype controls are shown only for I/R mice. Data represent mean ± SEM and are representative of at least 2 experiments; n = 4–6 mice per group. *P < 0.05; **P < 0.01.

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