Abstract
Increased concentrations of circulating chromatin, especially oligo-nucleosomes, are observed in sepsis, cancer and some inflammatory autoimmune diseases like systemic lupus erythematosus (SLE). In SLE, circulating nucleosomes mainly result from increased apoptosis and decreased clearance of apoptotic cells. Once released, nucleosomes behave both as an autoantigen and as a damage-associated molecular pattern (DAMP) by activating several immune cells, especially pro-inflammatory cells. Deoxyribonuclease 1 (DNase1) is a major serum nuclease whose activity is decreased in mouse and human lupus. Likewise, the mitochondrial chaperone tumor necrosis factor (TNF) receptor-associated protein-1 (Trap1) protects against oxidative stress, which is increased in SLE. Here, using wild type, DNase1-deficient and DNase1/Trap1-deficient mice, we demonstrate that DNase1 is a major serum nuclease involved in chromatin degradation, especially when the plasminogen system is activated. In vitro degradation assays show that chromatin digestion is strongly impaired in serum from DNase1/Trap1-deficient mice as compared to wild type mice. In vivo, after injection of purified chromatin, clearance of circulating chromatin is delayed in DNase1/Trap1-deficient mice in comparison to wild type mice. Since defective chromatin clearance may lead to chromatin deposition in tissues and subsequent immune cell activation, spleen cells were stimulated in vitro with chromatin. Splenocytes were activated by chromatin, as shown by interleukin (IL)-12 secretion and CD69 up-regulation. Moreover, cell activation was exacerbated when Trap1 is deficient. Importantly, we also show that cytokines involved in lupus pathogenesis down-regulate Trap1 expression in splenocytes. Therefore, combined low activities of both DNase1 and Trap1 lead to an impaired degradation of chromatin in vitro, delayed chromatin clearance in vivo and enhanced activation of immune cells. This situation may be encountered especially, but not exclusively, in SLE by the negative action of cytokines on Trap1 expression.
Highlights
Increased concentrations of circulating chromatin are observed in some inflammatory autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis, as well as in sepsis and cancers
Heparin supports the activity of the plasminogen system [36], the activity of which is reduced in SLE, resulting in impaired fibrinolysis and potentially leading to thrombosis, a frequent lupus manifestation [37]
Internucleosomal cleavage occurs, yielding accumulation of mono-nucleosomes. These results suggest that the cooperation between Deoxyribonuclease 1 (DNase1) and proteases naturally present in the serum is involved in the efficient degradation of chromatin
Summary
Increased concentrations of circulating chromatin are observed in some inflammatory autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis, as well as in sepsis and cancers. Extracellular nucleosomes behave as a damage-associated molecular pattern (DAMP) and are proinflammatory They induce activation of dendritic cells [6] and polymorphonuclear neutrophils (PMN) [7], leading to secretion of the key lupus cytokine interferon (IFN)-α [8] as well as proinflammatory cytokines [9] and the release of soluble CEACAM8 [10]. This was observed in mice and humans, both in healthy individuals and lupus patients, indicating that those cells have the capacity to respond to nucleosomes but that the key pathogenic event is an elevated nucleosome concentration in patients only. Nucleosomes were shown to bind laminin β1, which is aberrantly expressed in the glomerular basement membrane during lupus nephritis [11]
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