Interleukin‐10 release from astrocytes suppresses neuronal apoptosis via the TLR2/NFκB pathway in a neonatal rat model of hypoxic‐ischemic brain damage. Issue 6 (18th August 2017)

• Record Type: Journal Article
• Authors: He, Mu Lan; Lv, Ze Yu; Shi, Xia; Yang, Ting; Zhang, Yun; Li, Ting‐Yu; Chen, Jie
• Is Part Of: Journal of neurochemistry. Volume 142:Issue 6(2017)
• Page Start: 920
• Page End: 933
• Publication Date: 2017-08-18
• Subjects: astrocyte -- hypoxic‐ischemic brain damage -- interleukin‐10 -- nuclear factor kappa B -- toll‐like receptor 2; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.14126
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: The biological function of interleukin‐10 (IL‐10) and the relationship between IL‐10 secretion and the Toll‐like receptor 2 (TLR2) expression levels in the central nervous system following hypoxic‐ischemic brain damage (HIBD) are poorly understood. Here, we intend to elucidate the biological function and mechanism of IL‐10 secretion following HIBD. In this study, we used a neonatal rat model of HIBD and found that rats injected with adeno‐associated virus‐IL‐10‐shRNA (short hairpin RNA) exhibited partially impaired learning and memory function compared to rats administered adeno‐associated virus‐control‐shRNA. In vitro oxygen‐glucose deprivation (OGD) induced IL‐10 release from astrocytes but not from neurons. Pretreatment with exogenous recombinant IL‐10 alleviated OGD‐mediated apoptosis of neurons but not astrocytes. In addition, we also observed that hypoxic injury induced a marked increase in IL‐10 expression in astrocytes as a result of activation of the TLR2/phosphorylated nuclear factor kappa B (p‐NFκB) p65 signaling cascade; furthermore, this effect disappeared upon small interfering RNA targeting rat TLR2 gene (siTLR2) treatment. Pyrrolidinedithiocarbamate, an inhibitor of NFκB activation, reduced the IL‐10 expression levels in both OGD‐injured astrocytes in vitro and the hippocampi of HIBD rats in vivo but did not significantly affect TLR2 expression. Furthermore, a luciferase assay revealed that p‐NFκB p65 could bind the −1700/−1000 bp proximal region of the IL‐10 gene promoter to regulate IL‐10 secretion from astrocytes and that this interaction could be controlled by OGD treatment. These data suggest that HIBD induces IL‐10 secretion from astrocytes to exert a paracrine‐induced anti‐apoptotic effect on injured neurons via the TLR2/NFκB signaling pathway, which may improve learning and memory dysfunction after ischemic injury. Abstract : We propose the neuroprotective effect of IL‐10 and its mechanism of secretion via the following events. Activation of TLR2 facilitates the increased phosphorylation of NFκB p65, which induces an Program Files/YoudaoDict/7.1.0.0421/resultui/dict/evident release of IL‐10 from astrocytes to suppress neuronal apoptosis. We believe that understanding this novel activity of endogenous IL‐10 could lead to the development of new therapeutic approaches for treating hypoxic‐ischemic brain damage (HIBD).