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Lead modulation of macrophages causes multiorgan detrimental health effects

Significance Statement

It is well documented that the environmental toxicant lead (Pb) has detrimental effects on a number of organ systems.  With regard to the immune system, it has long been known that Pb decreases host defenses against pathogens and cancer.  Pb effects on humoral and cell-mediated immunity have been characterized.  However, there have been few reports documenting Pb’s impact on the innate immune system and specifically the macrophage.  Because of their ubiquitous systemic distribution and divergent phenotypes, Pb’s influences on cells of the monocyte/macrophage lineage have the ability to impact many organ systems.  Activated macrophages have a wide variety of subtypes that can be broadly divided into two main groups M1 (efficient at intracellular pathogen killing) and M2 (associated with allergic reactions and pulmonary inflammation).  The type of activated macrophages generated is highly dependent on the microenvironment surrounding the cells.  Skewing of T-cell help towards Th2 by Pb is now well known.  This skewing will decrease tissue concentrations of IFN-g and increase concentrations of IL-4.  Increased IL-4 concentrations in the macrophage microenvironment will result in generation of M2 type macrophages, which are not efficient in killing intracellular pathogens.  These cells do not produce nitric oxide (NO) and lack expression of the IFN-g inducible GTPases [immunity related guanosine triphosphatases (IRGS) and guanylate-binding proteins (GBPs)] found to be important for intracellular pathogen killing.  Pb treatment inhibited NO production by Con-A stimulated splenocytes and decreased tissue gene expression of IRGs and GBPs. M2 macrophage subsets are characterized by high expression of heme oxygenase-1 (HO-1), and Pb has been shown to increase expression of HO-1. All macrophage subsets possess both protective and damaging properties and in healthy tissues a certain homeostasis is maintained between the various subsets.  Disruption of this homeostasis by the environmental toxin, Pb, can lead to disease states, such as chronic inflammation, atherosclerosis, and cancer, etc.

Figure Legend

The accumulative effects of Pb shift macrophages toward M2 responses.  Pb increases oxidative stress lowering GSH and elevating the GSSH:GSH ratio.  This elevated ratio results in uncoupling of iNOS activity, via S-glutathionylation, yielding increased O2 and decreased NO production.  The Pb effect on heme synthesis and red cell destruction will increase Fe2+ and further increase oxidative stress (Fenton reaction) and HO-1 expression.   Skewing of T-cell help toward Th2 by Pb increases IL-4 and lowers IFN-g, thereby creating a microenvironment conducive to development of M2 type macrophage subsets and decreased expression of IFN-g inducible GTPases (IRGs and GBPs) involved in cell autophagy functions.

 

Lead modulation of macrophages causes multiorgan detrimental health effects - Global Medical Discovery

 

 

 

 

 

Kasten-Jolly J, Lawrence DA.

J Biochem Mol Toxicol. 2014 ;28(8):355-72.

Wadsworth Center, New York State Department of Health, Albany, NY, 12208, USA.

Abstract

The environmental toxicant lead (Pb) has detrimental effects on a number of organ systems, including the immune system. Pb exposure decreases host immune defenses against numerous microorganisms and cancer. Although Pb effects on humoral and cell-mediated immunity as well as on erythrocyte, neural, and renal pathophysiology have been well documented, there are few reports regarding Pb’s impact on innate immunity, which can affect multiorgan processes. This review focuses on Pb modulation of a key innate immune cell, the macrophage. The impact of Pb on macrophages in different organs, on immature versus mature macrophages, and on low versus high Pb concentrations is discussed. Pb decreases phagocytosis and chemotaxis of macrophages and affects nitric oxide production and eicosanoid metabolism in mature macrophages. Pretreatment of macrophages with Pb increases TNF-{Alpha} secretion after in vitro stimulation with lipopolysaccharide; however, Pb exposure decreases in vivo intracellular pathogen killing. More recent evidence from mouse studies indicates that even low, environmentally relevant, blood concentrations of Pb result in increased phagocytosis of erythrocytes and decreased expression of interferon-gamma-inducible GTPases, p65-GBP, and p47-IRG, which are necessary for intracellular pathogen killing. Taking into account the effects of Pb on macrophages, the review describes posited mechanisms to account for Pb-altered health effects; Pb effects on heme levels may play a key role as well as Pb’s preferential induction of helper type-2 T (Th2) cells and M2 macrophages, which is related to oxidative stress. The discussion links old findings with new, thereby adding new insight into the effects of Pb on  macrophages and the resultant compromised immunity and health.

© 2014 Wiley Periodicals, Inc.

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