Intracerebroventricular administration of lupus serum induces microglia activation and leukocyte adhesion in the cerebromicrovasculature of mice

Abstract

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.

Serum IgG-indcued microglial activation enhances neuronal cytolysis via the NO/sGC/PKG pathway in children with opsoclonus-myoclonus syndrome and neuroblastoma

“…Consistently, we and others found that IgG-induced neuronal cytolysis occurs in pediatric OMS rather than adult OMS [6,7]. Notably, increased microglial activation is not specific to only OMS, since previous literatures have documented that serum IgG from patients with PD [12] or ALS [13] enhances the activation of microglia and the production of NO, and serum IgG from patients with SLE induced behavioral changes are mediated by microglial activation [14][15][16]. Moreover, several autoantibodies found in patients with OMS [40][41][42][43] also exist in other diseases, such as autoantibody against glycine receptor in progressive encephalomyelitis with rigidity and myoclonus [42,44] or autoantibody against glutamic acid decarboxylase in stiff-person syndrome [44].…”

“…Moreover, the expression of microglial marker soluble CD14 and proinflammatory cytokines is enhanced in CSF from patients with pediatric OMS [10,11]. Additionally, serum IgG from patients or autoantibody existed in patients directly enhances microglial activation in PD [12], ALS [13] and SLE [14][15][16], or initially binds with astrocytes or neurons and further indirectly affects microglial activation [38,39]. Autoantibodies are also detectable in serum and CSF of children with OMS [25,26] and may be contained in serum IgG from children with OMS and NB in our study, although we did not identify these autoantibodies and autoantibodies include IgM besides IgG.…”

Serum IgG-induced microglial activation enhances neuronal cytolysis via the NO/sGC/PKG pathway in children with opsoclonus-myoclonus syndrome and neuroblastoma

“…Moreover, the expression of microglial marker soluble CD14 and proinflammatory cytokines is enhanced in CSF from patients with pediatric OMS [10,11]. Additionally, serum IgG from patients or autoantibody existed in patients directly enhances microglial activation in PD [12], ALS [13] and SLE [14][15][16], or initially binds with astrocytes or neurons and further indirectly affects microglial activation [43,44]. Autoantibodies are also detectable in sera and CSF of children with OMS [25,26] and may be contained in serum IgG from children with OMS and NB in our study, although we did not identify these autoantibodies and autoantibodies include IgM besides IgG.…”

“…Notably, increased microglial activation is not specific to only OMS, since previous literatures have documented that serum IgG from patients with PD [12] or ALS [13] enhances the activation of microglia and the production of NO, and serum IgG from patients with SLE induced behavioral changes are mediated by microglial activation [14][15][16]. Moreover, several autoantibodies found in patients with OMS [45][46][47][48] also exist in other diseases, such as autoantibody against glycine receptor in progressive encephalomyelitis with rigidity and myoclonus [47,49] or autoantibody against glutamic acid decarboxylase in stiff-person syndrome [49].…”

“…Notably, patients with pediatric OMS exhibit increased expression of a microglial marker and proinflammatory cytokines in cerebrospinal fluid (CSF) and some children with OMS are post-infectious [10,11]. Furthermore, serum IgG or autoantibody existed in patients enhances microglial activation in Parkinson disease (PD) [12], amyotrophic lateral sclerosis (ALS) [13] and systemic lupus erythematosus (SLE) [14][15][16]. Thus, it is reasonable to hypothesize that serum IgG from children with OMS and NB may impact the activation of microglia.…”