Soluble epoxide hydrolase modulates immune responses in activated astrocytes involving regulation of STAT3 activity

Abstract

Background Astrocyte activation is a common pathological feature in many brain diseases with neuroinflammation, and revealing the underlying mechanisms might shed light on the regulatory processes of the diseases. Recently, soluble epoxide hydrolase (sEH) has been proposed to affect neuroinflammation in brain injuries. However, the roles of astrocytic sEH in brains with neurodegeneration remain unclear. Methods The expression of astrocytic sEH in the brains of APPswe/PSEN1dE9 (APP/PS1) mice developing Alzheimer’s disease (AD)-like pathology was evaluated by confocal imaging. LPS-activated primary astrocytes with mRNA silencing or overexpression of sEH were used to investigate its regulatory roles in astrocyte activation and the induction of pro-inflammatory markers. Primary astrocytes isolated from a sEH knockout (sEH −/− ) background were also applied. Results The immunoreactivity of sEH was increased in activated astrocytes in parallel with the progression of AD in APP/PS1 mice. Our data from primary astrocyte cultures further demonstrate that the overexpression of sEH ameliorated, while the silencing of sEH mRNA enhanced, the lipopolysaccharides (LPS)-induced expression of pro-inflammatory markers, such as inducible nitric oxide, cyclooxygenase 2 (COX-2), and pro-inflammatory cytokines. These findings suggest that sEH negatively regulates astrocyte immune responses. Enhanced immune responses found in LPS-activated sEH −/− astrocytes also support the notion that the expression of sEH could suppress the immune responses during astrocyte activation. Similarly, sEH −/− mice that received intraperitoneal injection of LPS showed exacerbated astrocyte activation in the brain, as observed by the elevated expression of glial fibrillary acidic protein (GFAP) and pro-inflammatory markers. Moreover, our data show that the phosphorylation of the signal transducer and activator of transcription 3 (STAT3) was upregulated in activated astrocytes from sEH mouse brains, and the pharmacological blockade of STAT3 activity alleviated the pro-inflammatory effects of sEH deletion in LPS-activated primary astrocytes. Conclusions Our results provide evidence, for the first time, showing that sEH negatively regulates astrocytic immune responses and GFAP expression, while the underlying mechanism at least partly involves the downregulation of STAT3 phosphorylation. The discovery of a novel function for sEH in the negative control of astrocytic immune responses involving STAT3 activation confers further insights into the regulatory machinery of astrocyte activation during the development of neurodegeneration. Electronic supplementary material The online version of this article (10.1186/s12974-019-1508-2) contains supplementary material, which is available to authorized users.

Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TWEAK) Enhances Activation of STAT3/NLRC4 Inflammasome Signaling Axis through PKCδ in Astrocytes: Implications for Parkinson’s Disease

“…Additionally, the STAT3 pathway has been shown to contribute to inflammation-associated astrogliosis [ 65 , 66 , 67 , 68 ]. ROS production serves as a trigger for STAT3 activation [ 69 ], and the redox-sensitive kinase PKCδ is also involved in the phosphorylation of STAT3 in response to IL-6 exposure [ 70 ]. We first examined whether TWEAK induced the activation of STAT3 by determining the magnitude of pSTAT3 (Ser727) expression levels in U373 cells treated with TWEAK or vehicle (1% DMSO) for 24 h. WB analysis carried out using anti-pSTAT3 (Ser727) and anti-STAT3 antibodies indicated that TWEAK markedly increased pSTAT3 phosphorylation at site Ser727 in U373 cells ( Figure 2 E), while total STAT3 protein expression levels remained unchanged between all experimental groups.…”

ChK1 activation induces reactive astrogliosis through CIP2A/PP2A/STAT3 pathway in Alzheimer's disease

“…STAT3 is an important transcription factor. Activation of STAT3 regulates reactive astrogliosis, 34 induces GFAP 35 expression, and production of pro-inflammatory factors such as TNFα and IL-6. 36,37 However, the molecular In tumor cells, PP2A inactivation increases phosphorylation levels of STAT3-S727, activates STAT3, and leads to the proliferation of tumor cells.…”

Dextromethorphan Dampens Neonatal Astrocyte Activation and Endoplasmic Reticulum Stress Induced by Prenatal Exposure to Buprenorphine

“…Indeed, astrocyte activation is a double-edged sword that can be detrimental or beneficial to neuronal survival, which is similar to the multiple functions of microglial activation in neurodegenerative diseases. In many brain diseases, activated astrocytes provide support for damaged neuronal tissue through the release of neurotrophic factors and clearance of neurotoxic substances [37]. Thus, it is conceivable to consider astrocyte activation induced by prenatal exposure to buprenorphine as a defensive response.…”

“…Primary Astrocyte Cultures. Primary astrocyte cultured cells were derived from cortices of P1 neonates with different prenatal treatments; the primary astrocyte cultures were performed as described previously [37]. Briefly, cells were dissociated using an enzyme solution containing Dulbecco's modified Eagle's medium (DMEM), ethylenediaminetetraacetic acid (0.5 mmol/L), L-cysteine (0.2 mg/mL), papain (15 U/mL), and DNase I (200 μg/mL), followed by trituration.…”