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Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies against nuclear components. Lupus nephritis (LN) is the major cause of morbidity and mortality in patients with SLE. Central to the pathogenesis of SLE is the accumulation of cellular waste, especially apoptotic microparticles (MPs), which stimulates diverse immune reactions including the formation of neutrophil extracellular traps (NETs). In this study, we investigated the content of MPs from SLE patients with and without (active) LN, their capacity to stimulate NET release, and assessed the molecular mechanisms underlying MP-induced NETosis. MPs from SLE patients with biopsy-proven active LN, remissive LN, without LN, and healthy controls were characterized by flow cytometry. Isolated neutrophils were exposed to MPs derived from either patient plasma or apoptotic human umbilical vein endothelial cells, and NET release was quantified by immunofluorescence imaging, spectrofluorometry or an in-house developed NET ELISA. MPs from SLE patients with active LN contain higher levels of acetylated chromatin compared to MPs from those with remissive LN, without LN, or healthy controls. MPs enriched in hyperacetylated chromatin are more potent in inducing NETosis when compared to MPs containing moderate acetylated chromatin. The release of NETs in response to MPs occurs rapidly in a concentration-dependent manner and proceeds independent from the formation of reactive oxygen species (ROS). Our data suggest that MPs containing acetylated chromatin drive ROS-independent NET release in SLE patients with active LN, which may lead to the glomerular deposition of NETs and subsequent NET-driven LN.
Highlights
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies against nuclear antigens, such as nucleosomes, DNA, and histones [1]
Since aberrant NETosis has been associated with the development of lupus nephritis (LN) in SLE, we explored whether MPs from SLE patients with active LN differ and have a different NETosis-inducing capacity when compared to MPs from SLE patients with remissive LN or without LN
MPs from patients with active LN showed a higher forward and side scatter compared to MPs from patients with remissive LN or without LN (Figures 1D,E), suggesting that these MPs originate from apoptotic cells, since they are generally larger in size and have more content compared to MPs derived from resting or activated cells [31]
Summary
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies against nuclear antigens, such as nucleosomes, DNA, and histones [1]. The presence of nuclear antigens in the circulation of patients with SLE can be explained by increased apoptosis and/or an impaired clearance of apoptotic cells. MPs have been identified and characterized in plasma of SLE patients and were previously shown to be highly pro-inflammatory [15,16,17,18]. Autoantibodies against these apoptosis-associated histone modifications can be found in patients with SLE, suggesting that these modifications play a role in breaking the immune tolerance [5, 19,20,21]
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