Role of CCR2 in macrophage migration into the liver during acetaminophen-induced hepatotoxicity in the mouse

Dambach, Donna M.; Watson, Linda; Gray, Kevin R.; Durham, Stephen K.; Laskin, Debra L.

doi:10.1053/jhep.2002.33162

Cited by 263 publications

(225 citation statements)

References 43 publications

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“…The origin of hepatic CCL2 in acute liver injury is known to be both resident Kupffer cells and injured hepatocytes leading to the recruitment of monocytes/macrophages, NK cells, T cells and neutrophil granulocytes. 27 Moreover, hepatic-derived CCL2 is able to stimulate the expansion, mobilization and subsequent trafficking of bone marrow population of activated CD11b + F4/80 + monocytes/macrophages to the liver, accounting for the marked expansion in hepatic macrophage numbers seen after acute liver injury. 28 Pro-inflammatory, M1-polarized macrophages can contribute to the recruitment of additional inflammatory and other immune cells into the tissue, while M2-polarized macrophages are predominantly anti-inflammatory.…”

Section: Discussionmentioning

confidence: 99%

Acute organ failure following the loss of anti-apoptotic cellular FLICE-inhibitory protein involves activation of innate immune receptors

Gehrke

Mann

et al. 2014

Cell Death Differ

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Apoptosis signaling is involved in both physiological tissue homeostasis and acute and chronic diseases. The role of regulatory apoptosis signaling molecules and their organ-specific functions are less defined. Therefore, we investigated the loss of the antiapoptotic cellular FLICE-inhibitory protein (cFLIP) and the mechanisms of the resulting lethal organ failure in vivo using inducible knockout mice. These were generated by crossing floxed cFLIP mice to a tamoxifen inducible Rosa26-creERT2 mouse strain. Death following global loss of cFLIP resulted from liver failure, accumulation of M1-polarized macrophages and accompanying hepatic cell death and inflammation. Apoptosis was also prominent in immune cells, the kidney and intestinal epithelial cells (IECs) but not in cardiomyocytes. Cellular injury led to the release of damage-associated molecular patterns (DAMPs) and the induction of innate immune receptors including toll-like receptors (TLRs) 4 and 9, and stimulator of interferon genes (STING). Transplantation of bone marrow with intact cFLIP or depletion of macrophages prevented the phenotype of acute liver failure. Interestingly, compound deletion of cFLIP in bone marrow-derived cells and hepatocytes did not promote organ failure. Thus, cFLIP exerts a critical role in tissue homeostasis by preventing the activation of monocytic cells and innate immunity, which causes cell death and inflammation in susceptible tissues. These results encourage the development of organ-specific anti-apoptotic and antiinflammatory therapies in acute organ failure.

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Section: Discussionmentioning

confidence: 99%

Acute organ failure following the loss of anti-apoptotic cellular FLICE-inhibitory protein involves activation of innate immune receptors

Gehrke

Mann

et al. 2014

Cell Death Differ

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“…Therefore, we investigated whether MCP-1 is responsible for the production of mid-and latephase cytokines IL-8 and IL-6, respectively, induced by SEA stimulation of IMFs. The biological effects of MCP-1 are mostly mediated by binding to the CC chemokine receptor CCR-2 (49,50). Therefore, to understand the responsiveness of IMFs to MCP-1, we analyzed the surface expression of CCR-2 by flow cytometry on IMFs.…”

Section: Mcp-1 Is Responsible For Il-8 and Il-6 Production Induced Bymentioning

confidence: 99%

Monocyte Chemoattractant Protein-1 Production by Intestinal Myofibroblasts in Response to Staphylococcal Enterotoxin A: Relevance to Staphylococcal Enterotoxigenic Disease

Pinchuk¹,

Beswick²,

Saada³

et al. 2007

The Journal of Immunology

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Food poisoning due to staphylococcal enterotoxins A and B (SEA and SEB) affects hundreds of thousands of people annually. SEA and SEB induce massive intestinal cytokine production, which is believed to be the key factor in staphylococcal enterotoxin enteropathy. MHC class II molecules are the major receptors for staphylococcal enterotoxins. We recently demonstrated that normal human subepithelial intestinal myofibroblasts (IMFs) express MHC class II molecules. We hypothesized that IMFs are among the first cells to respond to staphylococcal enterotoxins and contribute to the cytokine production associated with staphylococcal enterotoxin pathogenesis. We demonstrated here that primary cultured IMFs bind staphylococcal enterotoxins in a MHC class II-dependent fashion in vitro. We also demonstrated that staphylococcal enterotoxins can cross a CaCo-2 epithelial monolayer in coculture with IMFs and bind to the MHC class II on IMFs. IMFs responded to SEA, but not SEB, exposure with 3- to 20-fold increases in the production of proinflammatory chemokines (MCP-1, IL-8), cytokines (IL-6), and growth factors (GM-CSF and G-CSF). The SEA induction of the proinflammatory mediators by IMFs resulted from the efficient cross-linking of MHC class II molecules because cross-linking of class II MHC by biotinylated anti-HLA-DR Abs induced similar cytokine patterns. The studies presented here show that MCP-1 is central to the production of other cytokines elicited by SEA in IMFs because its neutralization with specific Abs prevented the expression of IL-6 and IL-8 by IMFs. Thus, MCP-1 may play a leading role in initiation of inflammatory injury associated with staphylococcal enterotoxigenic disease.

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“…[5][6][7][8][9][10][11] The inflammatory mediators such as cytokines, chemokines, reactive oxygen, and nitrogen species released by Kupffer cells/macrophages have been implicated in APAP hepatotoxicity. [5][6][7][8][9][10] We have previously reported that natural killer (NK) and NKT cells, a major component of liver innate immune system, play a critical role in the severity and progression of APAP-induced liver injury by secreting cytokine interferon gamma (IFN-␥), modulating chemokine production and recruitment of inflammatory cells into the liver. 11 Our previous study also identified neutrophils as a major fraction of inflammatory cells in the liver from APAP-challenged mice.…”

mentioning

confidence: 99%

Neutrophil depletion protects against murine acetaminophen hepatotoxicity†‡

et al. 2006

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We previously reported that liver natural killer (NK) and NKT cells play a critical role in mouse model of acetaminophen (APAP)-induced liver injury by producing interferon gamma (IFN-␥) and modulating chemokine production and subsequent recruitment of neutrophils into the liver. In this report, we examined the role of neutrophils in the progression of APAP hepatotoxicity. C57BL/6 mice were given an intraperitoneal toxic dose of APAP (500 mg/kg), which caused severe acute liver injury characterized by significant elevation of serum ALT, centrilobular hepatic necrosis, and increased hepatic inflammatory cell accumulation. Flow cytometric analysis of isolated hepatic leukocytes demonstrated that the major fraction of increased hepatic leukocytes at 6 and 24 hours after APAP was neutrophils (Mac-1 ؉ Gr-1 ؉ ). Depletion of neutrophils by in vivo treatment with anti-Gr-1 antibody (RB6-8C5) significantly protected mice against APAP-induced liver injury, as evidenced by markedly reduced serum ALT levels, centrilobular hepatic necrosis, and improved mouse survival. The protection was associated with decreased FasL-expressing cells, cytotoxicity against hepatocytes, and respiratory burst in hepatic leukocytes. In intracellular adhesion molecule (ICAM)-1-deficient mice, APAP caused markedly reduced liver injury when compared with wild-type mice. The marked protection in ICAM-1-deficient mice was associated with decreased accumulation of neutrophils in the liver. Hepatic GSH depletion and APAP-adducts showed no differences among the antibody-treated, ICAM-1-deficient, and normal mice. In conclusion, accumulated neutrophils in the liver contribute to the progression and severity of APAP-induced liver injury. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).

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Role of CCR2 in macrophage migration into the liver during acetaminophen-induced hepatotoxicity in the mouse

Cited by 263 publications

References 43 publications

Acute organ failure following the loss of anti-apoptotic cellular FLICE-inhibitory protein involves activation of innate immune receptors

Acute organ failure following the loss of anti-apoptotic cellular FLICE-inhibitory protein involves activation of innate immune receptors

Monocyte Chemoattractant Protein-1 Production by Intestinal Myofibroblasts in Response to Staphylococcal Enterotoxin A: Relevance to Staphylococcal Enterotoxigenic Disease

Neutrophil depletion protects against murine acetaminophen hepatotoxicity†‡

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