BackgroundNeuropsychiatric manifestations are frequent in patients with systemic lupus erythematosus (SLE), yet the etiology and pathogenesis of brain damage in SLE remains unclear. Because the production of autoantibodies, formation and deposition of immunocomplexes are major serological characteristics of SLE, the elevated level of serum immunoglobulin may contribute to brain tissue injury of SLE. To testify this, in this study, we examined whether immunoglobulin G (IgG) in the serum of SLE patients affects the cellular functions in central nervous system and the potential mechanism.MethodsIn vivo intracerebral injection of SLE-serum in mouse was used to activate microglia and the production of pro-inflammatory cytokine was assessed by ELISA. Sera was divided into IgG and IgG depleted fractions, while IgG was further divided into Fc and Fab fragments to examine which part has an effect on microglia. Flow cytometry, immunofluorescence and quantitative PCR (qPCR) were used to verify the synergistic effect of B-cell activating factor (BAFF) on IgG stimulation of microglia.ResultsWe found that IgG in lupus sera can induce M1 activation of brain microglia following intraventricular injection into normal mice, and BAFF facilitates this process. In vitro, we identified that IgG bound to microglia through Fc rather than Fab fragments, and BAFF up-regulated the expression of Fc receptors (FcγR) on the surface of microglia, consequently, promote IgG binding to microglia.ConclusionOur results suggest that lupus serum IgG causes inflammatory responses of microglia by involving the Fc signaling pathway and the activity could be up-regulated by BAFF. Accordingly, disruption of the FcγR-mediated signaling pathway and blockade of microglia activation may be a therapeutic target in patients with neuropsychiatric lupus erythematosus.
Background: Central nervous system (CNS) involvement is commonly seen in the patients with system lupus erythematosus (SLE). Mechanisms underlying CNS damage in SLE remain largely unknown. Accumulating evidence suggest that activation of microglia in CNS plays an important role in the inflammatory responses in neurological diseases. The aim of this study is to examine the involvement of microglia in the CNS inflammatory responses induced by circulating serum of SLE patients. Methods: We performed intracerebroventricular (ICV) injection of serums collected from SLE patients or healthy controls to mice, and examined phenotypic changes of microglia, the levels of cytokines, chemokine and adhesion molecules in the brain. Intravital microscopy was used to observe leukocyte rolling and adhesion in the cerebromicrovasculature. We further examined whether minocycline can block inflammatory responses induced by SLE serum. In vitro experiments were conducted to examine whether IgGs from the sera of SLE patients or healthy control can activate the primary cultured microglia. Results: We found that ICV injection of SLE serum increases morphological activation of microglia in the cortex and hippocampus. Inflammatory mediators including pro-inflammatory cytokines (IL-1, IL-6 and TNF-α), chemokine (CCL2 and CCL5) and adhesion molecules (P-selectin and ICAM-1) were significantly elevated in the brains of SLE-serum-treated mice. Using intravital microscopy, we demonstrated that SLE serum promotes leukocyte rolling and adhesion. Furthermore, suppression of microglia activation by systemically using minocycline could decrease the levels of inflammatory molecular, and prevent leukocyte rolling and adhesion. The in vitro experiments revealed that IgG from SLE sera could be engulfed by microglia and stimulated the microglia to secret pro-inflammatory cytokines. Conclusion: Our data suggest that the activation of microglia, which promotes leukocyte adhesion to the brain microvasculature, is an important pathological mechanism of CNS involvement in SLE.
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