Accumulation of MDA epitopes plays a major role during diet-induced hepatic inflammation and can be ameliorated by administration of an anti-MDA antibody. (Hepatology 2017;65:1181-1195).

Atherosclerotic cardiovascular disease (CVD) is the leading cause of mortality worldwide 1,2 . Atherosclerotic plaque formation is initiated upon trapping of low-density lipoprotein (LDL) in the subendothelial space of large and medium size arteries that initially involves binding of LDL to heparan-sulfate proteoglycans (HSPGs) 3 , followed by a chronic inflammation and remodelling of the artery wall 3 . A Proliferation Inducing Ligand (APRIL), a cytokine produced by many cell types, binds to HSPGs 4 , but the physiology of this interaction is largely unknown. Here, we show that genetic ablation or antibody-mediated depletion of APRIL aggravates atherosclerosis in mice.Mechanistically, we demonstrate that APRIL confers atheroprotection via binding to heparan sulfate (HS) chains of heparan-sulfate proteoglycan 2 (HSPG2), which limits LDL retention, macrophage accumulation and necrotic core formation. Indeed, antibody-mediated depletion of APRIL in mice expressing HS-deficient HSPG2 had no effect on atherosclerosis development.Consistent with these data, treatment with a specific anti-APRIL antibody that promotes the binding of APRIL to HSPGs reduces experimental atherosclerosis. Furthermore, the serum levels of a previously unknown form of human APRIL protein that binds to HSPGs, which we termed non-canonical APRIL (nc-APRIL), are associated independently of traditional risk factors with long term (10-to 12-year follow up) cardiovascular mortality in patients with atherosclerosis. Our data reveal hitherto unknown properties of APRIL that have broad pathophysiological implications for vascular homeostasis.

The endolysosomal cysteine endoprotease cathepsin L is secreted from cells in a variety of pathological conditions such as cancer and arthritis. We compared the secretome composition and extracellular proteolytic cleavage events in cell supernatants of cathepsin L-deficient and wild-type mouse embryonic fibroblasts (MEFs). Quantitative proteomic comparison of cell conditioned media indicated that cathepsin L deficiency affects, albeit in a limited manner, the abundances of extracellular matrix (ECM) components, signaling proteins, and further proteases as well as endogenous protease inhibitors. Immunodetection corroborated that cathepsin L deficiency results in decreased abundance of the ECM protein periostin and elevated abundance of matrix metalloprotease (MMP)-2. While mRNA levels of MMP-2 were not affected by cathepsin L ablation, periostin mRNA levels were reduced, potentially indicating a downstream effect. To characterize cathepsin L contribution to extracellular proteolysis, we performed terminal amine isotopic labeling of substrates (TAILS), an N-terminomic technique for the identification and quantification of native and proteolytically generated protein N-termini. TAILS identified >1500 protein N-termini. Cathepsin L deficiency predominantly reduced the magnitude of collagenous cleavage sites C-terminal to a proline residue. This contradicts cathepsin L active site specificity and indicates altered activity of further proteases as a result of cathepsin L ablation.