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

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

doi:10.1172/jci40008

Cited by 167 publications

(182 citation statements)

References 62 publications

(61 reference statements)

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“…This, in turn, reduced production of TNF-α, IL-6, and reactive oxygen species by inflammatory monocytes and attenuated ischemia/ reperfusion injury. 27 Similarly, TLR9-mediated increases in DC-derived indoleamine 2,3-dioxygenase protected against experimental autoimmune diabetes mellitus. 28 Thus, the central role of TLR9 in many inflammatory diseases is suggestive of a possible role in atherosclerosis, but available reports would not allow foreseeing the direction of TLR9's involvement, as either pro-or antiatherosclerotic.…”

Section: Discussionmentioning

confidence: 99%

Protective Role for Toll-Like Receptor-9 in the Development of Atherosclerosis in Apolipoprotein E–Deficient Mice

Koulis

Chen

Hausding

et al. 2014

ATVB

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Objective— Atherosclerosis is driven by inflammatory reactions that are shared with the innate immune system. Toll-like receptor-9 (TLR9) is an intracellular pattern recognition receptor of the innate immune system that is currently under clinical investigation as a therapeutic target in inflammatory diseases. Here, we investigated whether TLR9 has a role in the development of atherosclerosis in apolipoprotein E–deficient (ApoE −/− ) mice. Approach and Results— Newly generated double-knockout ApoE −/− :TLR9 −/− mice and control ApoE −/− mice were fed a high-fat diet from 8 weeks and effects on lesion size, cellular composition, inflammatory status, and plasma lipids were assessed after 8, 12, 15, and 20 weeks. All 4 time points demonstrated exacerbated atherosclerotic lesion severity in ApoE −/− :TLR9 −/− mice, with a corresponding increase in lipid deposition and accumulation of macrophages, dendritic cells, and CD4 + T cells. Although ApoE −/− :TLR9 −/− mice exhibited an increase in plasma very low-density lipoprotein/low-density-lipoprotein cholesterol, the very low-density lipoprotein/low-density lipoprotein:high-density lipoprotein ratio was unaltered because of a parallel increase in plasma high-density lipoprotein cholesterol. As a potential mechanism accounting for plaque progression in ApoE −/− :TLR9 −/− mice, CD4 + T-cell accumulation was further investigated and depletion of these cells in ApoE −/− :TLR9 −/− mice significantly reduced lesion severity. As a final translational approach, administration of a TLR9 agonist (type B CpG oligodeoxynucleotide 1668) to ApoE −/− mice resulted in a reduction of lesion severity. Conclusions— Genetic deletion of the innate immune receptor TLR9 exacerbated atherosclerosis in ApoE −/− mice fed a high-fat diet. CD4 + T cells were identified as potential mediators of this effect. A type B CpG oligodeoxynucleotide TLR9 agonist reduced lesion severity, thus identifying a novel therapeutic approach in atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

Protective Role for Toll-Like Receptor-9 in the Development of Atherosclerosis in Apolipoprotein E–Deficient Mice

Koulis

Chen

Hausding

et al. 2014

ATVB

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“…Attempts to correlate the effects of aPC on the LPS response of DCs with alterations in the chemokine/cytokine milieu in the plasma compartment and whole spleen lysates or via direct detection of intracellular IL-12 as a key modulator of DC function were not informative. Recent reports on the antiinflammatory effects of IL-10 in liver injury (47,48) and in the suppression of graft-versus-host disease by CD8 + DCs suggest that the statistically significant augmentation of IL-10 levels may be biologically relevant and possibly result from the interaction of EPCR + DCs with T cells (49). How aPC treatment affects the above candidate mechanisms and how they might contribute to mitigating the lethal effects of LPS challenge remains to be clarified.…”

Section: Discussionmentioning

confidence: 99%

Activated protein C targets CD8+ dendritic cells to reduce the mortality of endotoxemia in mice

Kerschen

Hernández²,

Zogg³

et al. 2010

J. Clin. Invest.

104

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Activated protein C (aPC) therapy reduces mortality in adult patients with severe sepsis. In mouse endotoxemia and sepsis models, mortality reduction requires the cell signaling function of aPC, mediated through protease-activated receptor-1 (PAR1) and endothelial protein C receptor (EPCR; also known as Procr). Candidate cellular targets of aPC include vascular endothelial cells and leukocytes. Here, we show that expression of EPCR and PAR1 on hematopoietic cells is required in mice for an aPC variant that mediates full cell signaling activity but only minimal anticoagulant function (5A-aPC) to reduce the mortality of endotoxemia. Expression of EPCR in mature murine immune cells was limited to a subset

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“…CD11c+ dendritic cells (DCs) have been associated with resolution of liver injury (25,26) and share a number of cell surface markers with macrophages (27). The restorative macrophage subset at 72 h expressed only intermediate levels of CD11c (Fig.…”

Section: Gmentioning

confidence: 99%

Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis

Ramachandran

Pellicoro

Vernon

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

798

947

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Although macrophages are widely recognized to have a profibrotic role in inflammation, we have used a highly tractable CCl 4 -induced model of reversible hepatic fibrosis to identify and characterize the macrophage phenotype responsible for tissue remodeling: the hitherto elusive restorative macrophage. This CD11B hi F4/80 int Ly-6C lo macrophage subset was most abundant in livers during maximal fibrosis resolution and represented the principle matrix metalloproteinase (MMP) -expressing subset. Depletion of this population in CD11B promoter-diphtheria toxin receptor (CD11B-DTR) transgenic mice caused a failure of scar remodeling. Adoptive transfer and in situ labeling experiments showed that these restorative macrophages derive from recruited Ly-6C hi monocytes, a common origin with profibrotic Ly-6C hi macrophages, indicative of a phenotypic switch in vivo conferring proresolution properties. Microarray profiling of the Ly-6C lo subset, compared with Ly-6C hi macrophages, showed a phenotype outside the M1/M2 classification, with increased expression of MMPs, growth factors, and phagocytosis-related genes, including Mmp9, Mmp12, insulin-like growth factor 1 (Igf1), and Glycoprotein (transmembrane) nmb (Gpnmb). Confocal microscopy confirmed the postphagocytic nature of restorative macrophages. Furthermore, the restorative macrophage phenotype was recapitulated in vitro by the phagocytosis of cellular debris with associated activation of the ERK signaling cascade. Critically, induced phagocytic behavior in vivo, through administration of liposomes, increased restorative macrophage number and accelerated fibrosis resolution, offering a therapeutic strategy to this orphan pathological process.

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

Cited by 167 publications

References 62 publications

Protective Role for Toll-Like Receptor-9 in the Development of Atherosclerosis in Apolipoprotein E–Deficient Mice

Protective Role for Toll-Like Receptor-9 in the Development of Atherosclerosis in Apolipoprotein E–Deficient Mice

Activated protein C targets CD8+ dendritic cells to reduce the mortality of endotoxemia in mice

Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis

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