S100B Protein Stimulates Microglia Migration via RAGE-dependent Up-regulation of Chemokine Expression and Release

Abstract

The Ca 2؉ -binding protein of the EF-hand type, S100B, is abundantly expressed in and secreted by astrocytes, and release of S100B from damaged astrocytes occurs during the course of acute and chronic brain disorders. Thus, the concept has emerged that S100B might act an unconventional cytokine or a damage-associated molecular pattern protein playing a role in the pathophysiology of neurodegenerative disorders and inflammatory brain diseases. S100B proinflammatory effects require relatively high concentrations of the protein, whereas at physiological concentrations S100B exerts trophic effects on neurons. Most if not all of the extracellular (trophic and toxic) effects of S100B in the brain are mediated by the engagement of RAGE (receptor for advanced glycation end products). We show here that high S100B stimulates murine microglia migration in Boyden chambers via RAGE-dependent activation of Src kinase, Ras, PI3K, MEK/ERK1/2, RhoA/ROCK, Rac1/JNK/AP-1, Rac1/ NF-B, and, to a lesser extent, p38 MAPK. Recruitment of the adaptor protein, diaphanous-1, a member of the formin protein family, is also required for S100B/RAGE-induced migration of microglia. The S100B/RAGE-dependent activation of diaphanous-1/Rac1/JNK/AP-1, Ras/Rac1/NF-B and Src/Ras/PI3K/ RhoA/diaphanous-1 results in the up-regulation of expression of the chemokines, CCL3, CCL5, and CXCL12, whose release and activity are required for S100B to stimulate microglia migration. Lastly, RAGE engagement by S100B in microglia results in up-regulation of the chemokine receptors, CCR1 and CCR5. These results suggests that S100B might participate in the pathophysiology of brain inflammatory disorders via RAGEdependent regulation of several inflammation-related events including activation and migration of microglia. S100B is a Ca 2ϩ -binding protein of the EF-hand type abundantly expressed in astrocytes (1). S100B has been implicated in the regulation of astrocyte shape, migration, proliferation and differentiation via activation of the Src/PI3K module and PI3K-dependent stimulation of Akt and RhoA activities and hence of the supramolecular organization of F-actin (2). S100B also regulates the state of assembly of microtubules and type III intermediate filaments (3) and the cytosolic Ca 2ϩ concentration (4). In addition to having intracellular regulatory activities, S100B also exerts extracellular effects. Indeed, astrocytes secrete the protein constitutively and to a larger extent under the action of several stimuli including the proinflammatory cytokine, TNF-␣ (see for review Ref. 1). Moreover, levels of brain S100B are elevated in the aging brain and in several pathological conditions such as Alzheimer disease, brain infarct, epilepsy, and infectious diseases, as well as in Down syndrome (5, 6) in consequence of S100B human gene mapping to chromosome 21q22.3 (7). For example, hypertrophic astrocytes in peri-infarct areas and in neuritic plaques in Alzheimer disease and Down syndrome show elevated expression levels of S100B, and S100B can be detected outside hypert...

Transgenerational modification of hippocampus TNF-α and S100B levels in the offspring of rats chronically exposed to morphine during adolescence

“…According to these studies, a close relationship exists between TNF-α and S100B levels in brain tissues, and typically, these levels are altered accordingly (22,55,56). In our study, the hippocampus TNF-α levels were increased while the S100B levels were inversely reduced as a result of chronic morphine exposure.…”

“…The S100B levels in hippocampus tissue and cerebrospinal fluid increase during brain damage or pathophysiological situations, and the consequent behavioral symptoms (28,30,(54)(55)(56)(57) might be induced by glial cell activation through the RAGE-dependent pathway (22,58). According to these studies, a close relationship exists between TNF-α and S100B levels in brain tissues, and typically, these levels are altered accordingly (22,55,56).…”

“…This protein plays a key role in neuroinflammation as one of the markers of inflammatory diseases of the nervous system, such as Alzheimer's disease and Parkinson's disease (18)(19)(20). Studies have shown that S100B acts on receptors, such as the receptor for advanced glycation end products (RAGE), and its downstream pathways cause the production and secretion of inflammatory cytokines through the activation of NF-KB (21,22). In pathophysiological conditions, astrocytes and especially microglia release large amounts of TNF-α (23).…”

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“…Similar responses have been reported that Rac1 involved in regulating MAPK activation through p21-activated kinases 36 or JNK/AP1 pathway. 37 In contrast, FSP-1-stimulated Rac1 activation could not be inhibited by negative dominant MEK5, suggesting that Rac1 acts as an upstream of ERK5.…”

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