Johan Frostegard, Sweden
Karolinska Institutet IMMPresenter of 2 Presentations
PCSK9 IS ASSOCIATED WITH DISEASE ACTIVITY AND IMPLICATED IN IMMUNE ACTIVATION IN SYSTEMIC LUPUS ERYTHEMATOSUS.
Abstract
Background and Aims
LDL-levels are increased by Proprotein convertase subtilisin kexin 9 (PCSK9) which targets the LDL-receptor (LDLR). We recently reported that PCSK9 ameliorates dendritic cell (DC) activation by oxidized LDL (OxLDL), which is abundant in atherosclerotic plaques and also raised and associated with cardiovascular disease (CVD) in SLE. We here investigate the role of PCSK9 in SLE.
Methods
PCSK9-levels were determined by ELISA among SLE patients (n=109) and age- and sex-matched population-based controls (n=91). Common carotid intima-media thickness (IMT) and plaque occurrence were determined by B-mode ultrasound. Plaques were graded by echogenicity. Human peripheral blood monocytes from SLE patients or controls were differentiated into DCs. Effects of PCSK9 and its inhibition by silencing were studied.
Results
PCSK9-levels were non-significantly higher among SLE-patients as compared to controls but associated significantly with SLE disease activity, as determined by SLAM (0.020) or SLEDAI (0.0178). There was no association between PCSK9-levels and atherosclerosis as determined by IMT, prevalence of plaques or echolucent (potentially vulnerable) plaques. PCSK9 levels were significantly associated with CVD among SLE-patients but not after adjustment for age.
OxLDL induced PCSK9 in DCs and DC-maturation with increased expression of CD86 and HLA-DR. The effects were significantly stronger in DC from SLE patients than from controls. Silencing of PCSK9 abolished OxLDL-induced DC-maturation.
Conclusions
PCSK9 is associated with disease activity in SLE. One underlying cause could be OxLDL, promoting DC-activation which depends on PCSK9. OxLDL induces PCSK9, an effect which is higher among SLE-patients. PCSK9 could play an unexpected immunological role in SLE.
OXIDIZED PHOSPHOLIPIDS EXPOSING PHOSPHORYLCHOLINE INDUCE ACTIVATION OF MACROPHAGES AND T CELLS – IMPLICATIONS FOR ATHEROSCLEROSIS AND AUTOIMMUNE DISEASES
Abstract
Background and Aims
Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycerol-3-phosphoryocholine (Ox-PAPC) is a major phospholipid in oxidized LDL (increased in atherosclerosis and other autoimmune diseases including SLE.) Such lipids are increased in autoimmune disease as SLE and associated with disease activity and cardiovascular disease. Here, we studied the effect of Ox-PAPC on immune activation in connection with atherosclerosis and autoimmunity.
The aim is to investigate how oxidized lipids can contribue to autoimmunity.
Methods
Macrophages and T-cells from human peripheral blood or atherosclerotic plaques were stimulated with Ox-PAPC in absence or presence of mitochondrial reactive oxygen species inhibitor (mito tempo) or glutathione (GSH) inhibitor (BSO). phosphatidylcholine (PTC), GSH or oxidized glutathione (GSSG) were measured from plasma. Immune activation, apoptosis, ROS production, heat shock protein 60 (HSP60), IL-1 beta, and mitochondrial membrane potential were measured by flow cytometry and/or ELISA. The level of GSH or GSSG and phosphatidylcholine in cells or plasma of atherosclerotic patients was measured by colorimetric and fluorometric kit.
Results
Ox-PAPC induced a pro-inflammatory type of T-cell activation but also induced apoptosis at a higher concentration. The Ox-PAPC-induced-activation and apoptosis of T-cells was inhibited by the mito tempo, and the mito tempo or BSO inhibited inflammatory macrophage activation. Furthermore, mitochondrial membrane potential was increased in macrophages but not in T cells. The level of PTC, GSH and GSSG were significantly higher in atherosclerotic patients as compared to control groups.
Conclusions
OxPAPC is a cause of proinflammatory activation of T cells through a direct mechanism and of macrophages in atherosclerotic plaques. Inhibition of OxPAPC could be useful to maintain plaque stability.