Isolevuglandins promote autoimmunity and hypertension in systemic lupus erythematosus


Hypertension, vascular inflammation and renal inflammation are characteristic of systemic lupus erythematosus (SLE), a multisystem autoimmune disease that is complex and poorly understood. Oxidation products of arachidonic and other fatty acids, termed isolevuglandins (isoLG) lead to formation of post-translational protein modifications that are immunogenic. We demonstrate isoLG enrichment in dendritic cells (DCs), B cells, and plasma cells from juvenile female B6.SLE123 mice. In adult B6.SLE123 and NZBWF1 mice, isoLG adducts are enriched in plasma cells and splenic DCs compared to C57Bl/6 and NZW mice respectively. Treatment with the isoLG-scavenger 2-hydroxybenzylamine (2-HOBA) reduced blood pressure, improved renal function, and attenuated renal injury. Moreover, 2-HOBA reduced bone marrow plasma cells, total IgG levels, and anti-dsDNA antibody titers. We also demonstrate that mice with SLE generate specific IgG antibodies against isoLG adducted protein, confirming the immunogenicity of isoLG adducts. Finally, we found that isoLG adducted peptides are markedly enriched in monocytes from patients with SLE which was accompanied by an increase in superoxide production. These findings support a role of isoLG adducts in the genesis and maintenance of systemic autoimmunity and its associated hypertension in SLE. Scavenging of isoLGs promises to be a novel therapy for this disease.

Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease that affects approximately nine females for every male. Cardiovascular disease, particularly myocardial infarction, stroke, and hypertension are increased in SLE. In women with SLE the prevalence of hypertension is higher when compared to healthy controls. The mechanism of hypertension in SLE has been attributed to multiple factors including concomitant renal disease and side effects of medications but remains unexplained. Importantly, in a study of 235 patients with SLE, hypertension was not correlated with renal disease or serum complement levels, suggesting that the occurrence of hypertension in SLE can be independent of renal disease. Aside from the hypertension related to autoimmune disease, immune activation has also been implicated in both humans with essential hypertension and in several models of experimental hypertension. Immune cells, including macrophages, T cells, and B cells are present in the kidneys and vasculature. Cytokines released by these cells are implicated in vascular remodeling, vasoconstriction and sodium retention . Mice that lack T cells have a blunted hypertensive response to angiotensin II (ang II) or deoxycorticosterone acetate, and deletion of the RAG1 gene blunts hypertension and end-organ damage in rats with salt-sensitive hypertension. Furthermore, blockade of T cell costimulation by CTLA4-Ig inhibited the development of hypertension in mice, suggesting a critical role of antigen presenting cells (APCs), such as monocytes and DCs, in the initiation of hypertension.

SLE is a complex disease associated with hypertension and augmented cardiovascular risk. In the present study, we demonstrate that isoLGs play a causative role in hypertension and autoinflammation in a mouse model of SLE. The importance of isoLGs in the induction of essential hypertension and the associated renal and vascular inflammation suggests a shared pathway of autoimmunity between these conditions. While the role of isoLG in other autoimmune conditions has yet to be studied, scavenging of isoLGs with molecules such as 2-HOBA may be a useful strategy for the treatment of these conditions.

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