C5a/CD88 signaling alters blood-brain barrier integrity in lupus through nuclear factor-κB.
ABSTRACT Inflammation is a key factor in a number of neurodegenerative diseases including systemic lupus erythematosus. The complement system is an important mechanism in initiating and amplifying inflammation. Our recent studies demonstrate that C5a, a protein fragment generated during complement activation could alter the blood-brain barrier integrity, and thereby disturb the brain microenvironment. To understand the mechanism by which this occurs, we examined the effects of C5a on apoptosis, translocation of nuclear factor-κB (NF-κb) and the expression of Iκbα, MAPK, CREB and TJ protein, zona occludens (ZO-1) in mouse brain endothelial cells. Apoptosis was examined by DNA laddering and caspase 3 activity and the distribution of the ZO-1 and the p65 subunit of NF-κB were determined by immunofluorescence. Inhibition of CD88 reduced translocation of NF-κb into the nucleus, altered ZO-1 at the interfaces of neighboring cells, decreased caspase 3 activity and prevented apoptosis in these cells. Our results indicate that signaling through CD88 regulates the blood-brain barrier in a NF-κb-dependent manner. These studies suggest that the C5a receptor, CD88 is a promising therapeutic target that will reduce NF-κb-signaling cascades in inflammatory settings.
Article: Changes of the properties in the upper layers of human skin on treatment with models of different pharmaceutical formulations - an ex vivo ESR imaging study.[show abstract] [hide abstract]
ABSTRACT: The noninvasive method of spectral-spatial electron spin resonance imaging (ESRI) was used to obtain a polarity map of human skin. The spin probes TEMPO, TEMPOL, and CAT-1, which are considered to act as drug representatives, were applied as reporter molecules. The polarity in skin layers was described by means of the changes of the hyperfine splitting constant A(iso), which itself is a reflection of interactions at a molecular level, and the effect of polarity on the spatial distribution of spin probes in skin samples was studied. Analyses of ESR tomograms of two-phase systems finalized in a simplified description for the empiric interpretation of values of the isotropic hyperfine coupling constants A(iso) of spin probes in different layers of human skin. The simplified statement provides values for the probability of interactions of water molecules with the NO group of spin probes. This allows conclusions concerning the state of hydration of the spin probes in different layers of the skin and introduces the spatial polarity function as additional and valuable information for existing skin models.ChemMedChem 05/2008; 3(4):653-9. · 3.15 Impact Factor
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ABSTRACT: The complement inhibitor, Crry, which blocks both the classical and alternative pathways, alleviates CNS disease in the lupus model, MRL/MpJ-Tnfrsf6lpr (MRL/lpr) mice. To understand the role of the alternative pathway, we studied mice deficient in a key alternative pathway protein, complement factor B (fB). Immune deposits (IgG and C3) were reduced in the brains of MRL/lpr fB-deficient (fB-/-MRL/lpr) compared to fB-sufficient (MRL/lpr) mice, indicating reduced complement activation. Reduced neutrophil infiltration (22% of MRL/lpr mice) and apoptosis (caspase-3 activity was reduced to 33% of MRL/lpr mice) in these mice indicates that the absence of the alternative pathway was neuroprotective. Furthermore, expression of phospho (p)-Akt (0.16+/-0.02 vs. 0.35+/-0.13, p<0.03) was increased, while expression of p-PTEN (0.40+/-0.06 vs. 0.11+/-0.07, p<0.05) was decreased in fB-/-MRL/lpr mice compared to their MRL/lpr counterparts. The expression of fibronectin, laminin and collagen IV was significantly decreased in fB-/-MRL/lpr mice compared to MRL/lpr mice, indicating that in the lupus setting, tissue integrity was maintained in the absence of the alternative pathway. Absence of fB reduced behavioral alterations in MRL/lpr mice. Our results suggest that in lupus, the alternative pathway may be the key mechanism through which complement activation occurs in brain, and therefore it might serve as a therapeutic target for lupus cerebritis.European Journal of Immunology 07/2007; 37(6):1691-701. · 5.10 Impact Factor
Article: Blood-brain barrier damage as a risk factor for corticosteroid-induced psychiatric disorders in systemic lupus erythematosus.[show abstract] [hide abstract]
ABSTRACT: To clarify the incidence of and risk factors for corticosteroid-induced psychiatric disorders (CIPDs) in patients with systemic lupus erythematosus (SLE), we conducted a prospective study of 161 consecutive episodes in 155 inpatients with a SLE flare who were treated with corticosteroids. A subgroup of these patients, those who experienced a total of 22 episodes with current overt central nervous system manifestations of SLE (CNS-SLE), were excluded from follow-up. Results of clinical, laboratory, and neurologic tests (including electroencephalography, magnetic resonance imaging of the brain, and cerebrospinal fluid [CSF] analysis), performed within a week before corticosteroid administration, were assessed with regard to development of CIPDs. Within 8 weeks of corticosteroid administration, a diagnosis of CIPD was made for 14 (10.1%) of 139 episodes in 135 patients with a non-CNS-SLE flare. Using multiple logistic regression analysis, we identified positive Q(albumin) (CSF/serum albumin ratio; an indicator of blood-brain barrier [BBB] damage) (odds ratio [OR], 33.3; 95% confidence interval [CI], 3.64-304; p=0.002) and low serum levels of complements (OR, 0.91; 95% CI, 0.83-1.00; p=0.047) as independent risk factors for CIPDs. Positive Q(albumin) was detected in 45% (5 of 11) of episodes in which CIPDs developed. Compared with episodes in which no psychiatric events occurred, a higher level of Q(albumin) was found in episodes in which CIPDs developed, and an even higher level was noted in episodes with active CNS-SLE (Jonckheere-Terpstra test, p<0.001). Although no causal links have been proven, the results from the present study raise the possibility that BBB damage may be associated with SLE- and corticosteroid-induced behavioral changes.Psychoneuroendocrinology 04/2008; 33(3):395-403. · 5.81 Impact Factor