Oxidized phospholipid-induced inflammation is mediated by Toll-like receptor 2

Abstract

Oxidative tissue damage is a hallmark of many chronic inflammatory diseases. However, the precise mechanisms linking oxidative changes to inflammatory reactions remain unclear. Herein we show that Toll-like receptor 2 (TLR2) translates oxidative tissue damage into inflammatory responses by mediating the effects of oxidized phospholipids. Intraperitoneal injection of oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycero-phosphorylcholine (OxPAPC) resulted in upregulation of inflammatory genes in wild-type, but not in TLR2−/− mice. In vitro, OxPAPC induced TLR2 (but not TLR4)-dependent inflammatory gene expression and JNK and p38 signaling in macrophages. Induction of TLR2-dependent gene expression required reducible functional groups on sn-2 acyl chains of oxidized phospholipids, as well as serum co-factors. Finally, TLR2−/− mice were protected against carbontetrachloride-induced oxidative tissue damage and inflammation, which was accompanied by accumulation of oxidized phospholipids in livers. Together, our findings demonstrate that TLR2 mediates cellular responses to oxidative tissue damage and they provide new insights into how oxidative stress is linked to acute and chronic inflammation.

Relationship of Oxidized Phospholipids on Apolipoprotein B-100 to Cardiovascular Outcomes in Patients Treated With Intensive Versus Moderate Atorvastatin Therapy

“…Immune responses to OSEs, such as OxPLs, play a central role in the development of atherosclerosis (2). OxPLs are pro-atherogenic and upregulate pro-inflammatory molecules in macrophages and endothelial cells (5). OxPL are present on Lp(a), both in the lipid phase and covalently bound to apolipoprotein (a) (apo(a), and the kringle IV type 10 segment of apo(a) strongly influences their binding (6,19).…”

“…OxPLs are important contributors to early and late events in atherogenesis by activating pro-inflammatory genes in endothelial cells and macrophages (4), leading to inflammatory cascades in the vessel wall (5). Lipoprotein(a) [Lp(a)] is the major lipoprotein carrier of OxPL, which may impart pro-inflammatory properties (6,7).…”

Release and Capture of Bioactive Oxidized Phospholipids and Oxidized Cholesteryl Esters During Percutaneous Coronary and Peripheral Arterial Interventions in Humans

“…Polyunsaturated fatty acids(PUFA) on cholesteryl esters(CE) undergo similar modifications as the PUFA on phospholipids under oxidative stress. Such oxidized cholesteryl esters(OxCE), in which the PUFA is oxidized but not the cholesterol moiety, are also abundant in OxLDL and in atherosclerotic plaques(11-13) and have been shown to be biologically active initiating pro-inflammatory macrophage activation and promoting foam cell formation(14,15). …”

TLR2 deficiency attenuates skeletal muscle atrophy in mice

“…Accordingly, TLR2 deficiency suppresses the upregulation of cytokine expression and oxidative stress induced by pro-oxidants in the liver [16,17]. Although TLR2 mediates insulin resistance in skeletal 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 muscle by increasing inflammation [18,19], its pathophysiological role in skeletal muscle atrophy has not been determined.…”