Enhanced Immune System Activation and Arterial Inflammation Accelerates Atherosclerosis in Lupus-Prone Mice

Abstract

Objective-Premature atherosclerosis is a characteristic feature of systemic lupus erythematosus, a prototypic autoimmune disease. The principle cellular and molecular mechanisms which underlie such accelerated atherosclerosis are indeterminate. Methods and Results-The pathophysiology of lupus-mediated atherogenesis was evaluated in a novel animal model involving transplantation of bone marrow cells from the lupus prone strain gld into Ldl-r Ϫ/Ϫ mice. Diet-induced atherogenesis in lethally-irradiated Ldl-r Ϫ/Ϫ mice transplanted with gld bone marrow cells resulted in accelerated atherosclerosis (ϩ65%) as compared with control mice transplanted with wild-type marrow cells. Enhanced atherogenesis was associated with enhanced activation of both B and T lymphocytes and with arterial inflammation involving endothelial cell activation, monocyte recruitment, and accumulation of apoptotic debris, macrophages, and CD4 T cells, but was independent of plasma lipid levels and renal function. Conclusions-Our data support the contention that despite the absence of both disturbed cholesterol homeostasis and renal dysfunction in autoimmune gld3Ldl-r Ϫ/Ϫ mice, lupus disease induces enhanced activation of the immune system and acts locally on the vasculature to induce inflammation, together with accumulation of apoptotic debris, macrophages, and CD4 T cells, thereby accelerating plaque progression. Key Words: atherosclerosis Ⅲ lupus Ⅲ arterial inflammation Ⅲ immune system Ⅲ apoptotic cells T he risk of cardiovascular disease (CVD) is significantly increased in the prototypic autoimmune disease, systemic lupus erythematosus (SLE). 1,2 The mechanisms underlying premature CVD in SLE may be related to accelerated atherosclerosis. 3,4 Such accelerated atherosclerosis potentially involves a combination of autoimmune-specific mechanisms and traditional cardiovascular risk factors (dyslipidemia, renal failure, and inflammation), although the central mechanisms involved are indeterminate. 2 Moreover, as most SLE patients are on active therapy (corticosteroids and other pharmacological agents), such agents might interfere with the atherogenic process 5 and lead to confounding findings. Therefore, identification of the mechanisms that contribute to disease progression might allow optimization of therapeutic approaches for prevention of CVD in SLE patients. In this setting, development of murine models may facilitate evaluation of the specific impact of autoimmunity on atherosclerosis progression and of the underlying mechanisms involved.Genetic studies of various strains of lupus-prone mice have identified at least 30 chromosomal regions of interest reflecting the multifactorial aspect of SLE. 6 In this context the use of various strains of lupus-prone mice and the study of their impact on atherogenesis may highlight the key molecular mechanisms that promote autoimmune-accelerated atherosclerosis. Mouse strains defective for the Fas/Fas L pathway (gld, lpr) present lupus-like autoimmune disorders comparable to those of human SLE. 6,7 Indeed, ...

Macrophage Apoptosis Exerts Divergent Effects on Atherogenesis as a Function of Lesion Stage

“…9 Moreover, apoptotic cells may possess proinflammatory properties, in part as a result of the presence of oxidized phospholipids (oxPLs) at their surface, 10,11 which are known triggers of inflammatory responses in arterial tissues. 12 In this setting, studies of mice in which components of the apoptotic cell clearance machinery have been deleted 13 or of lupus-prone mice characterized by ineffective apoptotic cell clearance 14 have revealed that defective apoptotic cell clearance is associated with enhanced atherosclerotic plaque progression.…”

“…The transgene consists of the human hBcl-2 cDNA from pORF-hBcl-2 (InvivoGen, San Diego, Calif) cloned downstream of the mouse macrophage-specific promoter CD68 from pDRIVE-mCD68 (Invivogen All these procedures were performed as previously described 14,16 (see the Methods section in the online-only Data Supplement).…”

“…9 Moreover, apoptotic cells may possess proinflammatory properties, in part as a result of the presence of oxidized phospholipids (oxPLs) at their surface, 10,11 which are known triggers of inflammatory responses in arterial tissues. 12 In this setting, studies of mice in which components of the apoptotic cell clearance machinery have been deleted 13 or of lupus-prone mice characterized by ineffective apoptotic cell clearance 14 have revealed that defective apoptotic cell clearance is associated with enhanced atherosclerotic plaque progression.To understand the impact of macrophage apoptosis on atherosclerosis at both early and advanced stages of lesion progression, we first used a transgenic approach allowing specific protection of macrophages against apoptosis (CD68-hBcl-2 mice). With this approach, we demonstrated that macrophage apoptosis was antiatherogenic during the early stages of atherosclerosis, whereas macrophage cell death accelerated plaque progression in more advanced lesions.…”

Lipids rule: resetting lipid metabolism restores T cell function in systemic lupus erythematosus

“…Despite substantial clinical data on the effects of these inhibitors on glycemic control and other clinical parameters, there is a paucity of data in humans that comprehensively evaluates the whole body metabolic adaptation to pharmacologic inhibition of the renal SGLT2 cotransporter. In this issue of the JCI, results are presented from two elegantly conducted metabolic studies in individuals with T2D that evaluated the SGLT2 inhibitors, dapagliflozin and empagliflozin (6,7). Both studies were well designed, used sophisticated metabolic techniques, evaluated subjects with T2D, involved both acute and longer-term evaluation (two-and four-week observations), and evaluated whole body insulin sensitivity and endogenous hepatic glucose production in response to SGLT2 inhibition.…”

“…In the study by Merovci et al (6), the primary goal was to evaluate the impact of hyperglycemia and its reduction by SGLT2…”