Macrophages and Inflammatory Mediators in Chemical Toxicity: A Battle of Forces

Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, New Jersey 08854.
Chemical Research in Toxicology (Impact Factor: 3.53). 08/2009; 22(8):1376-85. DOI: 10.1021/tx900086v
Source: PubMed

ABSTRACT Macrophages function as control switches of the immune system, providing a balance between pro- and anti-inflammatory responses. To accomplish this, they develop into different subsets: classically (M1) or alternatively (M2) activated macrophages. Whereas M1 macrophages display a cytotoxic, proinflammatory phenotype, much like the soldiers of The Dark Side of The Force in the Star Wars movies, M2 macrophages, like Jedi fighters, suppress immune and inflammatory responses and participate in wound repair and angiogenesis. Critical to the actions of these divergent or polarized macrophage subpopulations is the regulated release of inflammatory mediators. When properly controlled, M1 macrophages effectively destroy invading pathogens, tumor cells, and foreign materials. However, when M1 activation becomes excessive or uncontrolled, these cells can succumb to The Dark Side, releasing copious amounts of cytotoxic mediators that contribute to disease pathogenesis. The activity of M1 macrophages is countered by The Force of alternatively activated M2 macrophages, which release anti-inflammatory cytokines, growth factors, and mediators involved in extracellular matrix turnover and tissue repair. It is the balance in the production of mediators by these two macrophage subpopulations that ultimately determines the outcome of the tissue response to chemical toxicants.

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    • "We considered the development of systemic inflammation as a result of the toxic state in BtDEF [32]. In inflammation, there is an increase of NF-kβ, which has previously been reported in this vitamin deficiency [33] and that enhances interleukin transcription, such as interleukin 6 (IL-6). "
    Molecular Genetics and Metabolism 09/2015; DOI:10.1016/j.ymgme.2015.08.009 · 2.63 Impact Factor
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    • "In contrast, M2 macrophages release anti-inflammatory mediators, down-regulating M1 responses and promoting tissue remodeling and angiogenesis. As the changes in the M1/M2 phenotypic balance can exacerbate inflammation systems and cause DILI (Laskin, 2009; Holt et al., 2008), we examined mRNA expression associated with macrophage phenotypes, M1 markers (iNOS), and M2 markers (Arg-1, Fizz1, and Ym1) (Fig. 6). APAP decreased LPSinduced iNOS and Arg-1 expression, and troglitazone also caused suppression in LPS-induced iNOS, Arg-1, Fizz1, and Ym1 expression, as shown Fig. 6. "
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    ABSTRACT: In recent years, attention has been paid to innate immune systems as mechanisms to initiate or promote drug-induced liver injury (DILI). Kupffer cells are hepatic resident macrophages and might be involved in the pathogenesis of DILI by release of pro- and anti-inflammatory mediators such as cytokines, chemokines, reactive oxygen species, and/or nitric oxides. The purpose of this study was to investigate alterations in mediator levels induced by hepatotoxic compounds in isolated Kupffer cells and discuss the relation between balance of each cytokine or chemokine and potential of innate immune-mediated DILI. Primary cultured rat Kupffer cells were treated with hepatotoxic (acetaminophen, troglitazone, trovafloxacin) or non-hepatotoxic (pioglitazone, levofloxacin) compounds with or without lipopolysaccharide (LPS). After 24 hr treatment, cell supernatants were collected and various levels of mediators released by Kupffer cells were examined. Although hepatotoxicants had no effect on the LPS-induced tumor necrosis factor-alpha (TNF-α) secretion, they enhanced the release of pro-inflammatory cytokine interleukin-1 beta (IL-1β) and suppressed the anti-inflammatory cytokines interleukin-6 (IL-6) and interleukin-10 (IL-10) induced by LPS. These cytokine shifts were not associated with switching the phenotypes of M1 and M2 macrophages in Kupffer cells. In conclusion, the present study suggested that the levels of some specific cytokines are affected by DILI-related drugs with LPS stimulation, and imbalance between pro- and anti-inflammatory cytokines, induced by the up-regulation of IL-1β and the down-regulation of IL-6 or IL-10, plays a key role in innate immune-mediated DILI.
    The Journal of Toxicological Sciences 05/2015; 40(3):389-404. DOI:10.2131/jts.40.389 · 1.29 Impact Factor
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    • "Recruited hepatic macrophages play an important role in liver repair after liver injury [29]. Immunostaining revealed that the number of F4/80-positive cells in WT livers and VEGFR1 TK-/- livers reduced compared with sham-controls, reaching a nadir at 6 h and then increasing gradually thereafter (n = 5–6 per group) (Fig. 3A, Fig. S4). "
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    ABSTRACT: Liver repair after acute liver injury is characterized by hepatocyte proliferation, removal of necrotic tissue, and restoration of hepatocellular and hepatic microvascular architecture. Macrophage recruitment is essential for liver tissue repair and recovery from injury; however, the underlying mechanisms are unclear. Signaling through vascular endothelial growth factor receptor 1 (VEGFR1) is suggested to play a role in macrophage migration and angiogenesis. The aim of the present study was to examine the role of VEGFR1 in liver repair and sinusoidal reconstruction after hepatic ischemia/reperfusion (I/R). VEGFR1 tyrosine kinase knockout mice (VEGFR1 TK-/- mice) and wild-type (WT) mice were subjected to hepatic warm I/R, and the processes of liver repair and sinusoidal reconstruction were examined. Compared with WT mice, VEGFR1 TK-/- mice exhibited delayed liver repair after hepatic I/R. VEGFR1-expressing macrophages recruited to the injured liver showed reduced expression of epidermal growth factor (EGF). VEGFR1 TK-/- mice also showed evidence of sustained sinusoidal functional and structural damage, and reduced expression of pro-angiogenic factors. Treatment of VEGFR1 TK-/- mice with EGF attenuated hepatoceullar and sinusoidal injury during hepatic I/R. VEGFR1 TK-/- bone marrow (BM) chimeric mice showed impaired liver repair and sinusoidal reconstruction, and reduced recruitment of VEGFR1-expressing macrophages to the injured liver. VEGFR1-macrophages recruited to the liver during hepatic I/R contribute to liver repair and sinusoidal reconstruction. VEGFR1 activation is a potential therapeutic strategy for promoting liver repair and sinusoidal restoration after acute liver injury.
    PLoS ONE 08/2014; 9(8):e105533. DOI:10.1371/journal.pone.0105533 · 3.23 Impact Factor
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