Cells of the innate immune system can be compared to cannons poised to release a diverse arsenal of oxidants that kill invading organisms but can frequently cause collateral damage through the oxidation of host cell molecules, including lipids. One of the oxidants produced in vivo is bleach. Yes, neutrophils, monocytes and some macrophages are enriched with myeloperoxidase, which acts to amplify the oxidant potential of these cells by converting hydrogen peroxide to hypochlorous acid and its conjugate base, hypochlorite (or bleach). These reactive chlorinating species (RCS) can chlorinate lipids, and the masked aldehyde of plasmalogens has proved to be the biggest (most reactive) target for the RCS projectile thus far.
Early studies demonstrated that RCS attack esterified and non-esterified fatty acid alkene groups and the primary amines of phosphatidylethanolamine and phosphatidylserine, leading to the production of lipid chlorohydrins and chloramines (1, 2). My lab focuses on RCS-targeting plasmalogens, and we found that RCS target the vinyl ether bond of plasmalogens, releasing the masked aldehyde as an α-chlorofatty aldehyde with a residual lysophospholipid by-product (3, 4). Our recent studies have shown that chlorinated fatty aldehyde is metabolized, giving rise to other chlorinated lipids, including α-chlorofatty acid and α-chlorofatty alcohol (5, 6). It is likely that these chlorinated lipid building blocks may be incorporated into complex lipids. Thus, through the initial volley of RCS attack on plasmalogens, a chlorinated lipidome is born!
These chlorinated lipids are novel molecules that are produced in response to the chemical arsenal released during inflammation, and it is quite possible that they may have important mechanistic roles in host tissue injury. Members of this chlorinated lipidome accumulate in activated neutrophils and monocytes and in infarcted myocardium and human atherosclerotic lesions (4, 7, 8). The primary plasmalogen-derived RCS products, α-chlorofatty aldehyde and unsaturated lysophosphatidylcholine, may propagate localized inflammatory responses because they are chemoattractants and elicit the surface expression of the phagocyte tethering molecule, P-selectin (4, 8). Also, HDL-associated α-chlorofatty aldehyde inhibits protective and vasoregulatory-important eNOS-derived NO production (9). These examples represent the beginning of our understanding of the role of these newly discovered lipids.
In the future, we should consider the significance of the accumulation of chlorinated lipids produced in humans due to environmental exposure to RCS (e.g., cleaning with bleach and exposure in swimming pools). Additionally, another oxidant cannon is fired as hypobromous acid by eosinophils and their peroxidase. Yes, parallel pathways exist for brominated lipid species produced by activated eosinophils. Furthermore, check out the ingredients of some soft drinks and sports drinks that include brominated vegetable oil. Not only do we produce these halogenated lipids as a result of the cannons of the innate immune system, but we are likely marching through this battlefield with self-inflicted daily environmental and nutritional exposure to reactive halogenating species and their halogenated lipid products.
1. Spickett, C. M. (2007) Chlorinated Lipids and Fatty Acids: An Emerging Role in Pathology. Pharmacol. Ther. 115, 400–409.
2. Messner, M. C., Albert, C. J., McHowat, J., and Ford, D. A. (2008) Identification of Lysophosphatidylcholine Chlorohydrin in Human Atherosclerotic Lesions. Lipids 43, 243–249.
3. Albert, C. J., Crowley, J. R., Hsu, F. F., Thukkani, A. K., and Ford, D.A. (2001) Reactive Chlorinating Species Produced by Myeloperoxidase Target the Vinyl Ether Bond of Plasmalogens: Identification of 2-Chlorohexadecanal. J. Biol. Chem. 276, 23733–23741.
4. Thukkani, A. K., Hsu, F. F., Crowley, J. R., Wysolmerski, R. B., Albert, C. J., and Ford, D. A. (2002) Reactive Chlorinating Species Produced during Neutrophil Activation Target Tissue Plasmalogens: Production of the Chemoattractant, 2-Chlorohexadecanal. J. Biol. Chem. 277, 3842–3849.
5. Anbukumar, D. S., Shornick, L. P., Albert, C. J., Steward, M. M., Zoeller, R. A., Neumann, W. L., and Ford, D. A. (2009) Chlorinated Lipid Species in Activated Human Neutrophils: Lipid Metabolites of 2-Chlorohexadecanal. J. Lipid Res. E-pub ahead of print, 10.1194/jlr.M003673.
6. Wildsmith, K. R., Albert, C. J., Anbukumar, D. S., and Ford, D. A. (2006) Metabolism of Myeloperoxidase-derived 2-Chlorohexadecanal. J. Biol. Chem. 281, 16849–16860.
7. Thukkani, A. K., Martinson, B. D., Albert, C. J., Vogler, G. A., and Ford, D. A. (2005) Neutrophil-mediated Accumulation of 2-ClHDA during Myocardial Infarction: 2-ClHDA-mediated Myocardial Injury. Am. J. Physiol. 288, H2955–H2964.
8. Thukkani, A. K., McHowat, J., Hsu, F. F., Brennan, M. L., Hazen, S. L., and Ford, D.A. (2003) Identification of a-Chloro Fatty Aldehydes and Unsaturated Lysophosphatidylcholine Molecular Species in Human Atherosclerotic Lesions. Circulation 108, 3128–3133.
9. Marsche, G., Heller, R., Fauler, G., Kovacevic, A., Nuszkowski, A., Graier, W., Sattler, W., and Malle, E. (2004) 2-Chlorohexadecanal Derived From Hypochlorite-Modified High-Density Lipoprotein-Associated Plasmalogen Is a Natural Inhibitor of Endothelial Nitric Oxide Biosynthesis. Arterioscler. Thromb. Vasc. Biol. 24, 2302–2306.
David A. Ford (email@example.com) is a professor in the department of biochemistry and molecular biology and director of the Center for Cardiovascular Research at Saint Louis University.