Abstract
IntroductionSystemic lupus erythematosus (SLE) is an autoimmune disease with chronic or episodic inflammation in many different organ systems, activation of leukocytes and production of pro-inflammatory cytokines. The heterodimer of the cytosolic calcium-binding proteins S100A8 and S100A9 (S100A8/A9) is secreted by activated polymorphonuclear neutrophils (PMNs) and monocytes and serves as a serum marker for several inflammatory diseases. Furthermore, S100A8 and S100A9 have many pro-inflammatory properties such as binding to Toll-like receptor 4 (TLR4). In this study we investigated if aberrant cell surface S100A8/A9 could be seen in SLE and if plasmacytoid dendritic cells (pDCs) could synthesize S100A8/A9.MethodsFlow cytometry, confocal microscopy and real-time PCR of flow cytometry-sorted cells were used to measure cell surface S100A8/A9, intracellular S100A8/A9 and mRNA levels of S100A8 and S100A9, respectively.ResultsCell surface S100A8/A9 was detected on all leukocyte subpopulations investigated except for T cells. By confocal microscopy, real-time PCR and stimulation assays, we could demonstrate that pDCs, monocytes and PMNs could synthesize S100A8/A9. Furthermore, pDC cell surface S100A8/A9 was higher in patients with active disease as compared to patients with inactive disease. Upon immune complex stimulation, pDCs up-regulated the cell surface S100A8/A9. SLE patients had also increased serum levels of S100A8/A9.ConclusionsPatients with SLE had increased cell surface S100A8/A9, which could be important in amplification and persistence of inflammation. Importantly, pDCs were able to synthesize S100A8/A9 proteins and up-regulate the cell surface expression upon immune complex-stimulation. Thus, S100A8/A9 may be a potent target for treatment of inflammatory diseases such as SLE.
Highlights
Systemic lupus erythematosus (SLE) is an autoimmune disease with chronic or episodic inflammation in many different organ systems, activation of leukocytes and production of pro-inflammatory cytokines
Real-time PCR and stimulation assays, we could demonstrate that plasmacytoid dendritic cell (pDC), monocytes and polymorphonuclear neutrophil (PMN) could synthesize S100A8/A9
We investigated if cell surface S100A8/A9 was altered in patients with active disease as compared to patients with inactive disease (SLEDAI < 4)
Summary
Systemic lupus erythematosus (SLE) is an autoimmune disease with chronic or episodic inflammation in many different organ systems, activation of leukocytes and production of pro-inflammatory cytokines. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by inflammation in several organ systems, B cell hyperactivity, autoantibodies, complement consumption and an ongoing type I interferon (IFN) production [1,2]. ICs could be endocytosed by the natural IFNa producing cells, the plasmacytoid dendritic cells (pDCs) and induce IFNa production through Toll-like receptor (TLR) 7 or TLR9 stimulation [21,22], which is considered to have a key role in the pathogenesis of SLE [23]. IFNa has many immunomodulatory functions such as inducing monocyte maturation [24], increasing IFNa production from NK cells [25], prolonging the survival of activated T cells [26] and differentiating B cells to plasma cells [27]
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