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

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 2

cDCs confer protection in I/R.

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cDCs confer protection in I/R. CD11c-DTR mice were administered PBS or D...
CD11c-DTR mice were administered PBS or DT via i.p. injection. Twelve hours later, mice received an i.v. injection of 1 × 107 WT cDCs or PBS and then underwent sham laparotomy or I/R. (A) Serum ALT levels and (B) representative liver H&E staining (original magnification, ×100) are shown at 12 hours after sham procedure or liver I/R. Nonviable patches of ischemic lobes are demarcated by dashed lines. CD11c-DTR mice were pretreated with DT or PBS 12 hours earlier and then subjected to sham laparotomy or 12 hours of I/R. (C) Serum cytokines levels were measured or (D) ischemic liver CD45+ NPCs were harvested and cultured overnight in media prior to measurement of supernatant cytokines. Data represent mean ± SEM (A, C, and D). Data in all panels are representative of at least 3 independent experiments; n = 4–6 mice per group. *P < 0.05; **P < 0.01; ***P < 0.001.