TGFß produced by IL-10 redirected astrocytes attenuates microglial activation.

ABSTRACT

While there clearly is an intimate relationship between astrocytes and microglia, few studies have examined these potentially dynamic interactions. In this study, cytokine-mediated communication between microglia and astrocytes under inflammatory conditions was investigated. We have previously shown that activated microglia produce Interleukin (IL)-10, a regulatory cytokine that plays an important role in resolving neuroinflammation. Nonetheless, the mechanism by which IL-10 attenuates pro-inflammatory cytokine expression in the brain is unclear. Here, we show that IL-10 redirected astrocytes regulate the activation of microglia in a transforming growth factor (TGF)-ß dependent manner. In support of this concept, astrocytes in the brain maintained higher IL-10 receptor (IL-10R1) expression and primary astrocytes in culture were markedly more sensitive to the anti-inflammatory effects of IL-10 compared with microglia. Moreover, studies using primary cultures and an astrocyte-microglia coculture system revealed that astrocytes mediated the anti-inflammatory effects of IL-10 on microglia through the production of TGFß. For instance, only when astrocytes were present did IL-10 stimulation reduce the expression of IL-1ß and increase expression of anti-inflammatory mediators fractalkine receptor (CX3 CR1) and interleukin 4 receptor-α (IL-4Rα) in microglia. Importantly, these IL-10-astrocyte dependent effects on microglia were blocked by a TGFß inhibitor. Furthermore, inhibition of TGFß signaling in the brain resulted in prolonged sickness behavior and amplified pro-inflammatory cytokine expression in mice challenged with lipopolysaccharide. Taken together, IL-10 stimulated the production of TGFß by astrocytes, which in turn, attenuated microglial activation. Overall, these findings provide novel insight into the mechanisms by which astrocytes modulate microglia under inflammatory conditions.