Cholesterol-Independent Suppression of Lymphocyte Activation, Autoimmunity, and Glomerulonephritis by Apolipoprotein A-I in Normocholesterolemic Lupus-Prone Mice

Abstract

Apolipoprotein A-I (ApoA-I), the major lipid-binding protein of high-density lipoprotein (HDL), can prevent autoimmunity and suppress inflammation in hypercholesterolemic mice by attenuating lymphocyte cholesterol accumulation and removing tissue oxidized lipids. However, whether ApoA-I mediates immune suppressive or anti-inflammatory effects in normocholesterolemic conditions and the mechanisms involved remain unresolved. We transferred bone marrow from SLE-prone Sle123 mice into normal, ApoA-I knockout (ApoA-I−/−) and ApoA-I transgenic (ApoA-Itg) mice. Increased ApoA-I in ApoA-Itg mice suppressed CD4+ T and B cell activation without changing lymphocyte cholesterol levels or reducing major ApoA-I-binding oxidized fatty acids. Unexpectedly, oxidized fatty acid peroxisome proliferator-activated receptor gamma (PPARγ) ligands 13-hydroxyoctadecadienoic acid (HODE) and 9-HODE were increased in lymphocytes of autoimmune ApoA-Itg mice. ApoA-I reduced Th1 cells independently of changes in CD4+FoxP3+ regulatory T cells or CD11c+ dendritic cell activation and migration. Follicular helper T cells, germinal center B cells and autoantibodies were also lower in ApoA-Itg mice. Transgenic ApoA-I also improved SLE-mediated glomerulonephritis. However, ApoA-I deficiency did not have opposite effects on autoimmunity or glomerulonephritis, possibly due to compensatory increases of ApoE on HDL. We conclude that although compensatory mechanisms prevent pro-inflammatory effects of ApoA-I deficiency in normocholesterolemic mice, increasing ApoA-I can attenuate lymphocyte activation and autoimmunity in SLE independently of cholesterol transport, possibly through oxidized fatty acid PPARγ ligands, and can reduce renal inflammation in glomerulonephritis.

Peptide serum markers in islet autoantibody-positive children

“…So far, to the best of our knowledge, APOC4 has not been described to play a role in the immune response. However, recent studies have discussed APOs such as APOM [38] in the context of autoimmunity [38][39][40], and future studies might unravel as-yet unidentified roles for APOC4.…”

High‐Density Lipoprotein in Lupus: Disease Biomarkers and Potential Therapeutic Strategy

“…L‐4F also improved the antiinflammatory functions of plasma HDL while reducing the proinflammatory effects of LDL. In a more recent study by Black et al, increased levels of Apo A‐I resulted in suppression of lymphocyte activation, IgG anti‐dsDNA autoantibodies, interferon‐γ–secreting CD4+ Th1 cells, and follicular T helper cells, along with improved glomerulonephritis in a normocholesterolemic murine model of SLE . Smith et al investigated whether reconstituted HDL can reverse the proinflammatory effects of lupus HDL by administering ETC‐642, an HDL mimetic composed of the Apo A‐I mimetic peptide (ESP24218) and phospholipid complex, in vivo to NZM2328 mice, a mouse model of lupus .…”

The A’s Have It

“…36 However, in a murine model of normocholesterolemic systemic lupus erythematosus, apoA-I overexpressing transgenic mice exhibited a reduction in Th1 cells that was independent of cholesterol or changes in regulatory T cells or dendritic cells. 37 Instead, apoA-I increased the production of oxidized metabolites of linoleic acid (eg, hydroxyoctadecadienoic acids) and arachidonic acid (eg, hydroxyeicosatetraenoic acids) that activate peroxisome proliferator-activated receptor-g. These studies suggest that the mechanism by which apoA-I regulates T-cell function may be context dependent and modified in the setting of hypercholesterolemia and obesity.…”