| First Author | Norden DM | Year | 2014 |
| Journal | Glia | Volume | 62 |
| Issue | 6 | Pages | 881-95 |
| PubMed ID | 24616125 | Mgi Jnum | J:209608 |
| Mgi Id | MGI:5568177 | Doi | 10.1002/glia.22647 |
| Citation | Norden DM, et al. (2014) TGFbeta produced by IL-10 redirected astrocytes attenuates microglial activation. Glia 62(6):881-95 |
| abstractText | 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)-beta 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 TGFbeta. For instance, only when astrocytes were present did IL-10 stimulation reduce the expression of IL-1beta and increase expression of anti-inflammatory mediators fractalkine receptor (CX3 CR1) and interleukin 4 receptor-alpha (IL-4Ralpha) in microglia. Importantly, these IL-10-astrocyte dependent effects on microglia were blocked by a TGFbeta inhibitor. Furthermore, inhibition of TGFbeta 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 TGFbeta 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. |
