ReviewImmunology

Enzymatically oxidized phospholipids assume center stage as essential regulators of innate immunity and cell death

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Science Signaling  26 Mar 2019:
Vol. 12, Issue 574, eaau2293
DOI: 10.1126/scisignal.aau2293

Figures

  • Fig. 1 Chemical mechanisms of lipid peroxidation.

    (A) The underlying process of lipid peroxidation. The process of hydrogen abstraction and oxygen addition that occurs during lipid oxidation, whether enzymatic or nonenzymatic, is the same. (B) A simplified diagram of nonenzymatic phospholipid oxidation.

    CREDIT: A. KITTERMAN/SCIENCE SIGNALING
  • Fig. 2 Direct oxidation of PLs by 12/15-LOX and indirect oxidation of PL by the Lands’ cycle to form eoxPLs.

    (A) Direct oxidation of membrane PLs is achieved by hydrogen abstraction on the Sn2 FA, usually arachidonic acid (AA), followed by oxygen insertion and reduction, thereby releasing a PL-hydroperoxide that is reduced by GPX4 to form a PL-OH. (B) Indirect oxidation of PLs by the Lands’ remodeling pathway occurs when phospholipase A2 (PLA2) hydrolysis of an Sn2 FA releases a substrate for oxidation by LOXs or COXs, forming an oxylipin which is then esterified back into lysoPLs by MBOATs or LPATs.

    CREDIT: A. KITTERMAN/SCIENCE SIGNALING
  • Fig. 3 eoxPLs support the generation of a prothrombotic surface on platelets, facilitating hemostasis.

    Activated platelets externalize aPLs and eoxPLs to form an electronegative surface that supports Ca2+-dependent binding and activation of coagulation factors, leading to thrombin formation.

    CREDIT: A. KITTERMAN/SCIENCE SIGNALING
  • Fig. 4 eoxPLs on the surface of resident macrophages facilitate clearance of apoptotic cells.

    In this mechanism, MFG-E8 binds to PS on apoptotic cells and macrophages, acting as a bridge to facilitate recognition and uptake by the macrophages themselves. Conversely, this mechanism prevents uptake of apoptotic cells by inflammatory monocytes that do not generate eoxPLs. Resident macrophages use the PS receptors TIM-4 and MFG-E8 to clear apoptotic cells, whereas inflammatory monocytes recognize PS with MFG-E8.

    CREDIT: A. KITTERMAN/SCIENCE SIGNALING
  • Fig. 5 eoxPL formation is required for ferroptosis.

    The following mechanism of how eoxPLs support ferroptosis has been proposed, although the detailed enzymology is not yet fully clear. First, the formation of PLs with long PUFA chains is facilitated by ACSL4. Then, oxidation of PE to form hydroperoxides is mediated by 15-LOX. Last, iron-dependent lipid peroxidation during ferroptosis involves insufficiency and shutdown of antioxidative enzymes such as GPX4 and LOX-mediated peroxidation that at least partially involves 15-LOX.

    CREDIT: A. KITTERMAN/SCIENCE SIGNALING

Tables

  • Table 1 Free radical products that form as oxPLs.

    MonosubstitutedPolyoxygenatedChain-shortened
    HydroperoxideDihydroperoxyω-Aldehydes
    HydroxyDihydroxyω-Carboxyl
    KetoHydroxy,
    hydroperoxy
    ω-Aldehyde-γ-
    hydroxy
    EpoxyKeto, hydroxyω-Carboxy-γ-hydroxy
    NitroalkanesHydrohydrinsω-Carboxy-γ-keto
    Nitro,hydroxyFuran
    OzonidesButanoyl (alkane)
    IsoprostanesButenoyl (alkene)
    F2-isoprostanes
    E2/D2-isoprostanes
    Epoxy-isoprostanes
    Isothromboxanes
    Isoleukotrienes

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