SR-A regulates the inflammatory activation of astrocytes.

Scavenger receptor Class A (SR-A) participates in the regulation of inflammatory processes against pathogens and in inflammatory stimulation. We have recently demonstrated the presence of SR-A in astrocytes, but its participation in their inflammatory response is unknown. Astrocytes regulate neuroinflammation through the regulation of microglial cell activation and the production of cytokines, neurotrophic factors, and reactive species. Using astrocytes from SR-A(-/-) mice in culture, we assessed the participation of SR-A in their inflammatory activation, evaluating the activation of IκB/NF-κB and MAPK signaling pathways and the production of nitric oxide (NO) and IL-1ß in response to SR-A ligands. In SR-A(-/-) astrocytes, lipopolysaccharide (LPS) induced higher levels of NO and reduced levels of IL-1ß compared to SR-A(+/+) cells. In addition, SR-A(-/-) astrocytes had a reduced basal and LPS-stimulated JNK phosphorylation, and a delayed activation on IκB/NF-κB signaling pathway in response to LPS. Moreover, inhibition of the ERK pathway reduced NO production by SR-A(-/-) cells, suggesting that this signaling pathway modulated LPS-induced NO production, an effect that depended on the presence of SR-A. Our results suggest that SR-A participates in the modulation of signaling pathways involved in the production of soluble molecules implicated in the neuroinflammatory response.

Scavenger receptor class A ligands induce secretion of IL1ß and exert a modulatory effect on the inflammatory activation of astrocytes in culture.

Class-A scavenger receptor (SR-A) is expressed by microglia, and we show here that it is also expressed by astrocytes, where it participates on their inflammatory activation. Astrocytes play a key role on the inflammatory response of the central nervous system, secreting several soluble mediators like cytokines and radical species. Exposure to SR ligands activated MAPKs and NF-κB signaling and increased production of IL1ß and nitric oxide (NO). IL1ß classically an inflammatory cytokine surprisingly did not increase but inhibited LPS+IFNγ-induced NO production by astrocytes. Our results suggest that SRs expressed by astrocytes participate in the modulation of inflammatory activation.

Aß potentiates inflammatory activation of glial cells induced by scavenger receptor ligands and inflammatory mediators in culture.

Alzheimer disease (AD) is a neurodegenerative disorder characterized by the accumulation of ß amyloid (Aß) aggregates. Aß induces the inflammatory activation of glia, inducing secretion of Interleukin 1ß (IL1ß), nitric oxide (NO) and superoxide radicals. The specific receptor responsible for the induction of inflammatory activation by Aß, is still an open question. We propose that scavenger receptors (SR) participate in the activation of glia by Aß. We assessed production of NO, synthesis of IL1ß and activation of ERK, JNK and NF-κB signaling pathways by Western blot, in primary rat glial cultures exposed to SR ligands (fucoidan and Poly I), LPS + IFNγ (LI), and Aß. Poly I but not fucoidan nor fibrillar Aß increased threefold NO production by astrocytes in a time-dependent manner. Fucoidan and Poly I increased 5.5- and 3.5-fold NO production by microglia, and co-stimulation with Aß increased an additional 60% NO induced by SR ligands. Potentiation by Aß was observed later for astrocytes than for microglia. In astrocytes, co-stimulation with Aß potentiated ERK and JNK activation in response to Fucoidan and Poly I, whereas it reduced induction of JNK activation by LI and left unaffected NF-κB activation induced by LI. Levels of pro-IL1ß in astrocytes increased with Aß, SR ligands and LI, and were potentiated by co-stimulation with Aß. Our results suggest that SRs play a role on inflammatory activation, inducing production of NO and IL1ß, and show potentiation by Aß. Potentiation of the inflammatory response of Aß could be meaningful for the activation of glia observed in AD.