Astrocytes Induce Hemeoxygenase-1 Expression in Microglia: A Feasible Mechanism for Preventing Excessive Brain Inflammation

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Abstract
Microglia are the major inflammatory cells in the brain, in which microglial inflammatory responses are modulated by interactions with other brain cells. Here, we show that astrocytes, the most abundant cells in the brain, can secrete one or more factors capable of modulating microglial activation by regulating the microglial levels of reactive oxygen species (ROS). Treatment of microglia with astrocyte culture-conditioned media (ACM) increased the expression level and activity of hemeoxygenase-1 (HO-1). ACM also induced nuclear translocation of the nuclear factor E2-related factor 2 transcription factor, increased the binding activity of the antioxidant response element (ARE), and enhanced HO-1 promoter activity in an ARE-dependent manner. Furthermore, treatment with ACM suppressed interferon-γ (IFN-γ)-induced ROS production, leading to reduced inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) release. In agreement with these results, mimickers of HO-1 products, such as bilirubin, ferrous iron, and a carbon monoxide-releasing molecule, reduced IFN-γ-induced iNOS expression and/or NO release. Finally, we found that the active component(s) in ACM was heat labile and smaller than 3 kDa. Together, these results suggest that astrocytes could cooperate with microglia to prevent excessive inflammatory responses in the brain by regulating microglial expression of HO-1 and production of ROS.