L5-LDL from ST-elevation myocardial infarction patients induces IL-1β production via LOX-1 and NLRP3 inflammasome activation in macrophages

• Published in: American journal of physiology. Heart and circulatory physiology 2017-02, Vol.312 (2), p.H265-H274
• Main Authors: Yang, Tzu-Ching, Chang, Po-Yuan, Lu, Shao-Chun
• Format: Article
• Language: English
• Subjects: Blotting, Western; CARD Signaling Adaptor Proteins; Caspase 1 - immunology; Cell Line; Cytoskeletal Proteins - genetics; Gene Knockdown Techniques; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) - genetics; Humans; Inflammasomes - immunology; Interleukin-1beta - genetics; Interleukin-1beta - immunology; Interleukin-6 - genetics; Interleukin-6 - immunology; Leukocytes, Mononuclear; Lipoproteins, LDL - immunology; Macrophages - immunology; NF-kappa B - immunology; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - immunology; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; RNA, Messenger - metabolism; Scavenger Receptors, Class E - genetics; Scavenger Receptors, Class E - immunology; ST Elevation Myocardial Infarction - genetics; ST Elevation Myocardial Infarction - immunology; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - immunology
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00509.2016

L5-LDL, the most electronegative LDL associated with major cardiovascular risks, significantly rises in patients with ST-segment elevation myocardial infarction (STEMI). The inflammatory nature of atherosclerotic vascular diseases has prompted us to investigate whether L5-LDL induces the production of inflammatory cytokines, especially vascular ischemia-related interleukin (IL)-1β, in the pathogenesis of STEMI. Clinical data showed that plasma levels of L5-LDL and IL-1β were higher in the STEMI patients than in the controls (P < 0.05). In THP-1-derived human macrophages, L5-LDL significantly increased the levels of both IL-1β and cleaved caspase-1, indicating the activation of NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasomes by L5-LDL. Knockdown of NLRP3 and its adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) resulted in decreased L5-LDL-induced IL-1β. Furthermore, knock down of the lectin-type oxidized LDL receptor (LOX-1) in THP-1 cells attenuated L5-LDL-induced activation of NF-κB and caspase-1, leading to subsequent inhibition of IL-1β in macrophages. Furthermore, blockade LOX-1 with neutralizing antibody also inhibited L5-LDL-induced IL-1β in human peripheral blood mononuclear cell-derived macrophages. In conclusion, L5-LDL induces IL-1β production in macrophages by activation of NF-κB and caspase-1 through the LOX-1-dependent pathway. This study represents the evidence linking L5-LDL and the inflammatory cytokine IL-1β in STEMI, and identifies L5-LDL as a novel therapeutic target in acute myocardial infarction. This study represents the evidence linking L5-LDL and the inflammatory cytokine IL-1β in ST-segment elevation myocardial infarction (STEMI). We elucidate the molecular mechanism underlying L5-LDL-induced production of IL-1β in macrophages. The results showed that L5-LDL induced activation of caspase-1 and NF-κB through the lectin-type oxidized LDL receptor (LOX-1)-dependent pathway, leading to the production of IL-1β.