Isolevuglandin-type lipid aldehydes induce the inflammatory response of macrophages by modifying phosphatidylethanolamines and activating the receptor for advanced glycation endproducts.
OBJECTIVE
Increased lipid peroxidation occurs in many conditions associated with inflammation. Because lipid peroxidation produces lipid aldehydes that can induce inflammatory responses through unknown mechanisms, elucidating these mechanisms may lead to development of better treatments for inflammatory diseases. We recently demonstrated that exposure of cultured cells to lipid aldehydes such as isolevuglandins (IsoLG) results in the modification of phosphatidylethanolamine (PE). We therefore sought to determine (i) whether PE modification by isolevuglandins (IsoLG-PE) occurred in vivo, (ii) whether IsoLG-PE stimulated the inflammatory responses of macrophages, and (iii) the identity of receptors mediating the inflammatory effects of IsoLG-PE.


RESULTS
IsoLG-PE levels were elevated in plasma of patients with familial hypercholesterolemia and in the livers of mice fed a high-fat diet to induce obesity and hepatosteatosis. IsoLG-PE potently stimulated nuclear factor kappa B (NFκB) activation and expression of inflammatory cytokines in macrophages. The effects of IsoLG-PE were blocked by the soluble form of the receptor for advanced glycation endproducts (sRAGE) and by RAGE antagonists. Furthermore, macrophages derived from the bone marrow of Ager null mice failed to express inflammatory cytokines in response to IsoLG-PE to the same extent as macrophages from wild-type mice.


METHODS
These studies are the first to identify IsoLG-PE as a mediator of macrophage activation and a specific receptor, RAGE, which mediates its biological effects.


CONCLUSIONS
PE modification by IsoLG forms RAGE ligands that activate macrophages, so that the increased IsoLG-PE generated by high circulating cholesterol levels or high-fat diet may play a role in the inflammation associated with these conditions.
1Division of Clinical Pharmacology, Vanderbilt University at Nashville, Nashville, Tennessee.
Lilu
L
Guo
1Division of Clinical Pharmacology, Vanderbilt University at Nashville, Nashville, Tennessee.
Zhongyi
Z
Chen
2Department of Pathology, Vanderbilt University at Nashville, Nashville, Tennessee.
Venkataraman
V
Amarnath
3Department of Medicine, Vanderbilt University at Nashville, Nashville, Tennessee.
Patricia G
PG
Yancey
4Division of Cardiology, Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California.
Brian J
BJ
Van Lenten
5GlycoMira Therapeutics, Salt Lake City, Utah.
Justin R
JR
Savage
6Department of Medicine, Oregon Health and Science University, Portland, Oregon.
Sergio
S
Fazio
3Department of Medicine, Vanderbilt University at Nashville, Nashville, Tennessee.|7Department of Pharmacology, Vanderbilt University at Nashville, Nashville, Tennessee.
MacRae F
MF
Linton
1Division of Clinical Pharmacology, Vanderbilt University at Nashville, Nashville, Tennessee.|7Department of Pharmacology, Vanderbilt University at Nashville, Nashville, Tennessee.|8Vanderbilt Institute of Chemical Biology, Vanderbilt University at Nashville, Nashville, Tennessee.
Sean S
SS
Davies
D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008055:Lipids / Q000737:chemistry; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000737:chemistry / Q000378:metabolism*; D011458:Prostaglandins E / Q000737:chemistry*; D011759:Pyrrolidines / Q000737:chemistry*; D000067759:Receptor for Advanced Glycation End Products / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*
D000447:Aldehydes; D008055:Lipids; D016328:NF-kappa B; D010714:Phosphatidylethanolamines; D011458:Prostaglandins E; D011759:Pyrrolidines; D000067759:Receptor for Advanced Glycation End Products; C483858:phosphatidylethanolamine