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Objectives Methylprednisolone (mPSL) pulse therapy is an essential treatment for systemic lupus erythematosus (SLE); however, it carries a risk of osteonecrosis of the femoral head (ONFH). A recent study has suggested that the pathogenesis of ONFH involves neutrophil extracellular trap (NET)-mediated microcirculation disorders. NETs are web-like substances released by activated neutrophils in response to stimuli such as infections. They are composed of DNA involving various neutrophil cytoplasmic antimicrobial proteins. NETs play a crucial role in innate immunity; however, excessive NET formation can lead to microcirculation disorders owing to their cytotoxicity and thrombogenicity. In BALB/c mice with imiquimod (IMQ)-induced lupus, mPSL pulse elevated plasma levels of prenylcysteine oxidase 1 (PCYOX1), an enzyme that produces NET inducers hydrogen peroxide and farnesal, resulting in increased NETs around the femoral head. Although ischemia was observed in the femoral head, IMQ-plus-mPSL-treated BALB/c mice did not develop ONFH. PCYOX1 is abundant in very-low-density lipoproteins (VLDL). This study aimed to demonstrate that hyperlipidemia promotes NET formation in the blood.Methods SLE was induced by the TLR7 agonist IMQ in Apo E mutant C.KOR/StmSlc-Apoeshl mice (n=8), which exhibit a marked increase in VLDL. Five of them were given mPSL. Three were given PBS instead. BALB/c mice were treated similarly as controls (with mPSL pulse: n=6, without mPSL pulse: n=4). Lipid analysis was conducted using HPLC. Plasma PCYOX1 levels were measured by ELISA. NET-forming neutrophils were detected by FCM using Gr-1 and Sytox green. The activities of superoxide dismutase (SOD) and catalase in the plasma were compared between C.KOR/StmSlc-Apoeshl and BALB/c mice.Results In IMQ-plus-mPSL-treated C.KOR/StmSlc-Apoeshl mice, total cholesterol and triglyceride levels, particularly triglyceride levels, were elevated but not in the other groups. The peak fraction was consistent with the VLDL fraction. Plasma levels of PCYOX1 were significantly increased in both IMQ-plus-mPSL-treated C.KOR/StmSlc-Apoeshl and BALB/c mice. In contrast, circulating NETs were increased only in IMQ-plus-mPSL-treated C.KOR/StmSlc-Apoeshl mice. The SOD and catalase activities in plasma were much lower in C.KOR/StmSlc-Apoeshl mice than in BALB/c mice.Abstract PO:01:009 Figure 1Conclusions Hyperlipidemia promotes NET formation in the blood following mPSL pulse in lupus mice. PCYOX1 and antioxidant enzymes may be involved in the underlying mechanisms.