AUTHOR=Liu Ting , Han Song , Dai Qingqing , Zheng Jiayin , Liu Cui , Li Shujuan , Li Junfa 

TITLE=IL-17A-Mediated Excessive Autophagy Aggravated Neuronal Ischemic Injuries via Src-PP2B-mTOR Pathway

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.02952

DOI=10.3389/fimmu.2019.02952

ISSN=1664-3224

ABSTRACT=<p>We previously reported that astrocyte-derived proinflammatory cytokine interleukin (IL)-17A could aggravate neuronal ischemic injuries and strength autophagy both in oxygen-glucose deprivation (OGD)/reoxygenation (R)-treated neurons and peri-infarct region of mice with middle cerebral artery occlusion (MCAO)/reperfusion (R)-simulated ischemic stroke. In this study, the role and molecular mechanism of IL-17A in autophagy were further explored under ischemic condition. We found that exogenous addition of rmIL-17A remarkably (<italic>P</italic> &lt; 0.001) decreased cell viability, which companying with the increases of LC3 II accumulation (<italic>P</italic> &lt; 0.05 or 0.01) and Beclin 1 levels (<italic>P</italic> &lt; 0.05 or 0.001), and reduction of p62 levels (<italic>P</italic> &lt; 0.01 or 0.001) in OGD/R-treated cortical neurons (<italic>n</italic> = 6). The levels of P-mTOR (Ser 2448) (<italic>P</italic> &lt; 0.001) and P-S6 (Ser 240/244) (<italic>P</italic> &lt; 0.01) significantly decreased without the involvement of Akt, ERK1/2 and AMPK in cortical neurons under rmIL-17A and OGD/R treatments (<italic>n</italic> = 6). Interestingly, the co-IP analysis exhibited that PP2B and mTOR could be reciprocally immunoprecipitated; and the addition of rmIL-17A increased their interactions, PP2B activities (<italic>P</italic> &lt; 0.001), P-Src (<italic>P</italic> &lt; 0.001), and P-PLCγ1 (<italic>P</italic> &lt; 0.01) levels in OGD/R-treated neurons (<italic>n</italic> = 6 or 5). The PP2B inhibitor Cyclosporin A blocked the induction of excessive autophagy (<italic>P</italic> &lt; 0.05 or &lt;0.001) and increased cell viability (<italic>P</italic> &lt; 0.001) after OGD/R and rmIL-17A treatments (<italic>n</italic> = 6). In addition, the ICV injection of IL-17A neutralizing mAb could attenuate autophagy levels (<italic>P</italic> &lt; 0.01 or 0.001, <italic>n</italic> = 6) and improve neurological functions (<italic>P</italic> &lt; 0.01 or 0.001, <italic>n</italic> = 10) of mice after 1 h MCAO/R 24 h or 7 d. These results suggested that IL-17A-mediated excessive autophagy aggravates neuronal ischemic injuries via Src-PP2B-mTOR pathway, and IL-17A neutralization may provide a potential therapeutic effect for ischemic stroke.</p>