Oxidized phospholipids (OxPL) are ubiquitous, are formed in many inflammatory tissues, including atherosclerotic lesions, and frequently mediate proinflammatory changes1. Because OxPL are mostly the products of non-enzymatic lipid peroxidation, mechanisms to specifically neutralize them are unavailable and their roles in vivo are largely unknown. We previously cloned the IgM natural antibody E06, which binds to the phosphocholine headgroup of OxPL, and blocks the uptake of oxidized low-density lipoprotein (OxLDL) by macrophages and inhibits the proinflammatory properties of OxPL2,3,4. Here, to determine the role of OxPL in vivo in the context of atherogenesis, we generated transgenic mice in the Ldlr−/− background that expressed a single-chain variable fragment of E06 (E06-scFv) using the Apoe promoter. E06-scFv was secreted into the plasma from the liver and macrophages, and achieved sufficient plasma levels to inhibit in vivo macrophage uptake of OxLDL and to prevent OxPL-induced inflammatory signalling. Compared to Ldlr−/− mice, Ldlr−/−E06-scFv mice had 57–28% less atherosclerosis after 4, 7 and even 12 months of 1% high-cholesterol diet. Echocardiographic and histologic evaluation of the aortic valves demonstrated that E06-scFv ameliorated the development of aortic valve gradients and decreased aortic valve calcification. Both cholesterol accumulation and in vivo uptake of OxLDL were decreased in peritoneal macrophages, and both peritoneal and aortic macrophages had a decreased inflammatory phenotype. Serum amyloid A was decreased by 32%, indicating decreased systemic inflammation, and hepatic steatosis and inflammation were also decreased. Finally, the E06-scFv prolonged life as measured over 15 months. Because the E06-scFv lacks the functional effects of an intact antibody other than the ability to bind OxPL and inhibit OxLDL uptake in macrophages, these data support a major proatherogenic role of OxLDL and demonstrate that OxPL are proinflammatory and proatherogenic, which E06 counteracts in vivo. These studies suggest that therapies inactivating OxPL may be beneficial for reducing generalized inflammation, including the progression of atherosclerosis, aortic stenosis and hepatic steatosis.
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This work was supported by NIH Grants: HL088093 (X.Q., S.T., C.K.G., K.L., Y.I.M. and J.L.W.), HL086559 (J.L.W.), HL119828 (J.L.W. and S.T.), HL055798 (S.T., J.L.W., Y.I.M., K.L. and C.C.H.), HL136275 (S.T., J.L.W. and Y.I.M.), R35 HL135737 (J.L.W. andY.I.M.), HL055798 and HL112276 (C.C.H.), HL20948 (J.G.M.), DRC P30 DK063491 (P.L.M.), P42 ES010337 (P.L.M.), P30 CA23100 (P.L.M.), Center for Human Nutrition grant 550015400 (J.G.M.) and Leducq Foundation Transatlantic Grants to J.L.W. and C.K.G. X.Q. was supported in part by a Grant-in-Aid from American Heart Association and D.E.G. was supported in part by an American Heart Association post-doctoral grant (13POST16990031).
Nature thanks N. Leitinger, A. R. Tall and the other anonymous reviewer(s) for their contribution to the peer review of this work.