Article

Macrophages and Tissue Injury: Agents of Defense or Destruction?

Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey 08854, USA.
Annual Review of Pharmacology (Impact Factor: 18.37). 11/2010; 51(1):267-88. DOI: 10.1146/annurev.pharmtox.010909.105812
Source: PubMed

ABSTRACT

The past several years have seen the accumulation of evidence demonstrating that tissue injury induced by diverse toxicants is due not only to their direct effects on target tissues but also indirectly to the actions of resident and infiltrating macrophages. These cells release an array of mediators with cytotoxic, pro- and anti-inflammatory, angiogenic, fibrogenic, and mitogenic activity, which function to fight infections, limit tissue injury, and promote wound healing. However, following exposure to toxicants, macrophages can become hyperresponsive, resulting in uncontrolled or dysregulated release of mediators that exacerbate acute tissue injury and/or promote the development of chronic diseases such as fibrosis and cancer. Evidence suggests that the diverse activity of macrophages is mediated by distinct subpopulations that develop in response to signals within their microenvironment. Understanding the precise roles of these different macrophage populations in the pathogenic response to toxicants is key to designing effective treatments for minimizing tissue damage and chronic disease and for facilitating wound repair.

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    • "Recent studies demonstrated that macrophages develop into distinct, functional phenotypes: the proinflammatory (M1) type and the anti-inflammatory (M2) type[5]. Macrophage polarization is a critical feature in various diseases such as atherosclerosis, obesity, fibrosis, and cancer[6]. Unfortunately, the cellular and molecular events underlying progression towards NASH, a more progressive and inflammatory disease phenotype, remain poorly understood. "
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    ABSTRACT: Opuntia ficus indica (L.) is a popular edible plant that possesses considerable nutritional value and exhibits diverse biological actions including anti-inflammatory and anti-diabetic activities. In this study, we hypothesized that DWJ504, an extract of Opuntia ficus indica seed, would ameliorate hepatic steatosis and inflammation by regulating hepatic de novo lipogenesis and macrophage polarization against experimental non-alcoholic steatohepatitis. Mice were fed a normal diet (ND) or a high-fat diet (HFD) for 10 weeks. DWJ504 (250, 500 and 1000 mg/kg) or vehicle (0.5% carboxymethyl cellulose) were orally administered for the last 4 weeks of the 10-week HFD feeding period. DWJ504 treatment remarkably attenuated HFD-induced increases in hepatic lipid content and hepatocellular damage. DWJ504 attenuated increases in sterol regulatory element-binding transcription factor 1 (SREBP-1) and carbohydrate-responsive element-binding protein (ChREBP) expression and a decrease in carnitine palmitoyltransferase 1A (CPT-1A). While DWJ504 augmented peroxisome proliferator-activated receptor alpha (PPAR-α) protein expression, it attenuated PPAR-γ expression. Moreover, DWJ504 promoted hepatic M2 macrophage polarization as indicated by attenuation of the M1 marker genes and enhancement of M2 marker genes. Finally, DWJ504 attenuated expression of toll-like receptor 4 (TLR4), nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), TIR-domain-containing adapter inducing interferon β (TRIF) and interferon-β (IFN-β) levels. Our results demonstrate that DWJ504 prevented intrahepatic lipid accumulation, induced M2 macrophage polarization, and suppressed the TLR4-mediated inflammatory signaling pathway. Thus, DWJ504 has therapeutic potential in the prevention of non-alcoholic fatty liver disease.
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    • "Host-defense cells generate a diversity of lipid-derived mediators that are involved in the response to tissue damage and inflammation: for example, they are a major source of eicosanoids such as prostaglandin E 2 , which cause local vasodilation and nociceptor sensitization, and act as signals to recruit blood-borne immune cells to injury sites (Laskin et al., 2011). However, a growing body of evidence indicates that host-defense cells can also release bioactive lipids that attenuate rather than instigate pain and inflammation. "
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    ABSTRACT: Macrophages are multi-faceted phagocytic effector cells that derive from circulating monocytes and undergo differentiation in target tissues to regulate key aspects of the inflammatory process. Macrophages produce and degrade a variety of lipid mediators that stimulate or suppress pain and inflammation. Among the analgesic and anti-inflammatory lipids released from these cells are the fatty acid ethanolamides (FAEs), which produce their effects by engaging nuclear peroxisome proliferator activated receptor-α (PPAR-α). Two members of this lipid family, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), have recently emerged as important intrinsic regulators of nociception and inflammation. These substances are released from the membrane precursor, N-acylphosphatidylethanolamine (NAPE), by the action of a NAPE-specific phospholipase D (NAPE-PLD), and in macrophage are primarily deactivated by the lysosomal cysteine amidase, N-acylethanolamine acid amidase (NAAA). NAPE-PLD and NAAA regulate FAE levels, exerting a tight control over the ability of these lipid mediators to recruit PPAR-α and attenuate the inflammatory response. This review summarizes recent findings on the contribution of the FAE-PPAR-α signaling complex in inflammation, and on NAAA inhibition as a novel mechanistic approach to treat chronic inflammatory disorders.
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    • "Findings that MMP inhibitors such as doxycyline and illomastat attenuate SM-induced respiratory lesions in rats, demonstrate the importance of proteases in vesicant-induced lung injury (Anderson et al., 2009). Alternatively activated antiinflammatory/wound repair M2 macrophages play a role in the resolution of lung injury [reviewed in Laskin et al., 2011]. Exaggerated responses of M2 macrophages are thought to contribute to the development of fibrosis. "
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    ABSTRACT: Exposure of humans and animals to vesicants, including sulfur mustard (SM) and nitrogen mustard (NM), causes severe and debilitating damage to the respiratory tract. Both acute and long term pathological consequences are observed in the lung following a single exposure to these vesicants. Evidence from our laboratories and others suggest that macrophages and inflammatory mediators they release play an important role in mustard-induced lung injury. In this paper, the pathogenic effects of SM and NM on the lung are reviewed, along with the potential role of inflammatory macrophages and mediators they release in mustard-induced pulmonary toxicity.
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