S100B protein activates a RAGE‐dependent autocrine loop in astrocytes: implications for its role in the propagation of reactive gliosis

Abstract

Extracellular S100B dramatically increases after brain injury. While low S100B levels are neuroprotective, micromolar S100B levels have shown in vitro to activate microglia and facilitate neuronal death. In astrocytes, S100B exposure activates nuclear factor kappa B (NF-jB) and induces proinflammatory mediators. On microglia and neurons S100B effects are essentially mediated by receptor for advanced glycation end products (RAGE)/NF-jB, but it is not clear if these intracellular cascades are activated by different S100B levels in astrocytes and whether increased extracellular S100B is sufficient to induce reactive gliosis. A better understanding of these pathways is essential for developing successful strategies to preserve the beneficial S100B effects after brain injury. Here, we show that microglia-depleted cultured astrocytes exposed to S100B mimicked several features of reactive gliosis by activating RAGE/Rac-1-Cdc42, RAGE/Erk-Akt or RAGE/NF-jB-dependent pathways. S100B effects include RAGE/Rac1-Cdc42-dependent astroglial hypertrophy and facilitation of migration as well as increased mitosis. S100B exposure improved the astrocytic survival to oxidative stress, an effect that requires Erk/Akt. S100B also activates NF-jB in a dose-dependent manner; increases RAGE proximal promoter transcriptional activity and augmented endogenous RAGE expression. S100B-exposed astrocytes showed a proinflammatory phenotype with expression of Toll-like receptor 2 (TLR 2), inducible nitric oxide synthase (iNOS) and interleukin 1-beta (IL-1b), and facilitated neuronal death induced by oxygen-glucose deprivation. In vivo, intracerebral infusion of S100B was enough to induce an astroglial reactive phenotype.Together, these findings demonstrate that extracellular S100B in the micromolar level activates different RAGE-dependent pathways that turn astrocytes into a pro-inflammatory and neurodegenerative phenotype.

S100B as a Potential Biomarker and Therapeutic Target in Multiple Sclerosis

“…Astrocyte activation has been observed during LPC-induced demyelination [25], and here, we show that astrocytes abundantly secrete S100B when exposed to the demyelinating agent. Moreover, excess of extracellular S100B levels may induce autocrine astrocytic activation that turns astrocytes into a proinflammatory and neurodegenerative phenotype [53]. In this situation, astrocytes secrete pro-inflammatory factors, which are known inhibitors of oligodendrocyte precursor cell proliferation and maturation, following demyelination in MS [54].…”

Pattern recognition receptors in chronic pain: Mechanisms and therapeutic implications

“…RAGE protein expression is present in rodent astrocyte primary cultures (Ponath et al, 2007;Villarreal et al, 2014). While protein expression of RAGE is normally below the detection level in resting astrocytes in vivo, RAGE immunoreactivity has been shown in astrocytes in the brain from AD patients and in the spinal cord from ALS patients (Brett et al, 1993;Casula et al, 2011;Sasaki et al, 2001), suggesting the potential involvement of astrocytic RAGE in neuroinflammation.…”

“…Furthermore, the activation of RAGE by S100β stimulation of cultured astrocytes resulted in the upregulation of iNOS and IL-1β via NFkB recruitment, which was blocked by the addition of a RAGE neutralizing antibody (Villarreal et al, 2014). In vivo, intracerebral infusion of S100β induced a reactive phenotype of astrocytes, highlighting a potential role for astrocytic RAGE in neuroinflammation (Villarreal et al, 2014). Therefore, it is quite possible that astrocytic RAGE also participates in the neuroinflammation and central sensitization induced by centrally released DAMP molecules in response to peripheral pathologies.…”

Neuroanatomical Mapping of s100 Immunoreactivity Reviewed

“…In contrast to the periventricular areas, GFAP-IR and S100B-IR colocalization in astrocytes was lower in cortical areas maybe because of its state of activation since GFAP is a marker for activated astrocytes [41,42]. Thus, one possible hypothesis is that under normal conditions, astrocytes in the periventricular areas remain more active than in the cerebral cortex.…”