Strawberry notch homolog 2 regulates the response to interleukin-6 in the central nervous system

Abstract

Background The cytokine interleukin-6 (IL-6) modulates a variety of inflammatory processes and, context depending, can mediate either pro- or anti-inflammatory effects. Excessive IL-6 signalling in the brain is associated with chronic inflammation resulting in neurodegeneration. Strawberry notch homolog 2 (Sbno2) is an IL-6-regulated gene whose function is largely unknown. Here we aimed to address this issue by investigating the impact of Sbno2 disruption in mice with IL-6-mediated neuroinflammation. Methods Mice with germline disruption of Sbno2 (Sbno2−/−) were generated and crossed with transgenic mice with chronic astrocyte production of IL-6 (GFAP-IL6). Phenotypic, molecular and transcriptomic analyses were performed on tissues and primary cell cultures to clarify the role of SBNO2 in IL-6-mediated neuroinflammation. Results We found Sbno2−/− mice to be viable and overtly normal. By contrast GFAP-IL6 × Sbno2−/− mice had more severe disease compared with GFAP-IL6 mice. This was evidenced by exacerbated neuroinflammation and neurodegeneration and enhanced IL-6-responsive gene expression. Cell culture experiments on primary astrocytes from Sbno2−/− mice further showed elevated and sustained transcript levels of a number of IL-6 stimulated genes. Notably, despite enhanced disease in vivo and gene expression both in vivo and in vitro, IL-6-stimulated gp130 pathway activation was reduced when Sbno2 is disrupted. Conclusion Based on these results, we propose a role for SBNO2 as a novel negative feedback regulator of IL-6 that restrains the excessive inflammatory actions of this cytokine in the brain.

Transcriptomics and translatomics identify a robust inflammatory gene signature in brain endothelial cells after ischemic stroke

“…In our study, the gene coding for a negative regulator of this pathway, Socs3 , was also highly overexpressed in endothelial cells after ischemia (Additional file 6 : Table S3). Moreover, we detected endothelial upregulation of Strawberry notch homolog 2 ( Sbno2 ), which is a negative regulator of IL-6 signaling [ 23 ], suggesting a controlled regulation of the active signaling pathways. Ischemia also induced strong upregulation of the gp130 cytokine family, interleukin-11 ( Il11 ) (Additional file 6 : Table S3), which promotes proliferation of cells expressing the gp130/IL11RA receptor and it is involved in cardiovascular fibrosis [ 24 ].…”

Oligonol ameliorates liver function and brain function in the 5 × FAD mouse model: transcriptional and cellular analysis

“…We also found 20 decreased genes, including Ralbp1, related to mitochondrial function and decreased neuroinflammation; 131,132 Slc38a10, related to the upregulation of cell survival and the homeostasis of neurotransmitters such as GABA, dopamine, serotonin, and glutamate; 133 Ppard, associated with the protection of axonal injury and cell growth and the regulation of immune response; 134 Paqr3, related to the regulation of energy metabolism, and Golgi apparatus; 135 Fbxo7, related to the upregulation of pyramidal neuronal function with Pink1; 136,137 Myo9b, related to the maintenance of the dendrite morphology of neurons; 138 Abca7, associated with the downregulation of the phagocytosis process in glia, and the process of Alzheimer's disease; 139,140 Sbno2, related to the downregulation of interleukin-6 secretion, and the suppression of inflammation; 141,142 and Snrnp70, related to the inhibition of amyotrophic lateral sclerosis and motoneuronal degeneration 143,144 in the 5 × FAD mouse hippocampus after oligonol treatment.…”