The innate immune response to products of phospholipid peroxidation

Abstract

Lipid peroxidation occurs in the context of many physiological processes but is greatly increased in various pathological situations. A consequence of phospholipid peroxidation is the generation of oxidation-specific epitopes, such as phosphocholine of oxidized phospholipids and malondialdehyde, which form neo-self determinants on dying cells and oxidized low-density lipoproteins. In this review we discuss evidence demonstrating that pattern recognition receptors of the innate immune system recognize oxidation-specific epitopes as endogenous damage-associated molecular patterns, allowing the host to identify dangerous biological waste. Oxidation-specific epitopes are important targets of both cellular and soluble pattern recognition receptors, including toll-like and scavenger receptors, C-reactive protein, complement factor H, and innate natural IgM antibodies. This recognition allows the innate immune system to mediate important physiological house keeping functions, for example by promoting the removal of dying cells and oxidized molecules. Once this system is malfunctional or overwhelmed the development of diseases, such as atherosclerosis and age-related macular degeneration is favored. Understanding the molecular components and mechanisms involved in this process, will help the identification of individuals with increased risk of developing chronic inflammation, and indicate novel points for therapeutic intervention. This article is part of a Special Issue entitled: Oxidized phospholipids-their properties and interactions with proteins.

Fig. 1

Schematic representation of a dying cell bound by cellular and soluble PRRs that recognize different OSEs. Several OSEs are present in the membranes of dying cells, including phosphocholine (PC) of oxidized phosphatidylcholine, oxidized phosphatidylserine (OxPS), oxidized cardiolipin (OxCL), malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) adducts. Similarly, carboxyethylpyrrole (CEP) adducts are present on oxidatively damaged photoreceptors. Several PRRs of innate immunity recognize OSEs including the scavenger receptor CD36, CRP and IgM natural antibody (NAb) EO6, which bind PC; SR-A, CFH and IgM NAb NA-17, which bind MDA-adducts; the IgM NAb LRO1 that binds OxCL, CD36 binding OxPS, and TLR2 that binds CEP-adducts. B1 cell derived natural IgM with specificity for 4-HNE have also been identified.

Fig. 2

Model of competition between CFH and CFHR1/3 on MDA-decorated surfaces. (A) CFH binds to MDA on the surface of apoptotic cells, where it promotes factor I-mediated cleavage of C3b into iC3b. (B) CFHR1 and 3 lack a complement regulatory function but contain potential MDA-binding motifs and may therefore compete with CFH for MDA binding, leading to reduced anti-inflammatory iC3b generation on MDA-decorated surfaces.