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      Wip1 regulates blood-brain barrier function and neuro-inflammation induced by lipopolysaccharide via the sonic hedgehog signaling signaling pathway.

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          Abstract

          The blood brain barrier (BBB) is a diffusion barrier that maintains the brain environment. Wip1 is a nuclear phosphatase induced by many factors and involved in various stresses, tumorigenesis, organismal aging, and neurogenesis. Wip1's role in BBB integrity has not been thoroughly investigated. The purpose of the present study was to investigate the effect and mechanism of Wip1 on lipopolysaccharide (LPS)-induced BBB dysfunction and inflammation in an in vitro BBB model. The in vitro BBB model was established by co-culturing human brain-microvascular endothelial cells and human astrocytes and then exposing them to 1μg/ml LPS for 6, 12, 18, 24, and 48h. Wip1 expression was significantly elevated by LPS treatment. Knockdown of Wip1 aggravated the increased permeability and decreased transepithelial electrical resistance, protein expression of ZO-1, and occludin induced by LPS. Wip1 silencing augmented the elevated inflammatory cytokines TNF-α, IL-1β, IL-12, and IL-6 of the BBB induced by LPS, whereas overexpression of Wip1 showed a contrary effect. Sonic hedgehog signaling (SHH) was activated by Wip1 overexpression and inhibited by Wip1 silencing. Additionally, activating or inhibiting the SHH pathway by purmorphamine or cyclopamine, respectively, abolished the Wip1-induced changes in transepithelial electrical resistance and permeability and inflammatory responses in the LPS-injured BBB model. Our results demonstrate that Wip1 may protect the BBB against LPS-induced integrity disruption and inflammatory response through the SHH signaling pathway.

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          Author and article information

          Journal
          Mol. Immunol.
          Molecular immunology
          Elsevier BV
          1872-9142
          0161-5890
          January 2018
          : 93
          Affiliations
          [1 ] No. 2 Department of Neurology, Cangzhou Central Hospital, No. 16 Xinhua Western Road, Cangzhou City, Hebei Province, China.
          [2 ] No. 2 Department of Neurology, Cangzhou Central Hospital, No. 16 Xinhua Western Road, Cangzhou City, Hebei Province, China. Electronic address: jiaxiuf_336@163.com.
          Article
          S0161-5890(17)30519-9
          10.1016/j.molimm.2017.09.020
          29128669
          587ee2cc-eacb-4ce7-a58c-d29a35f6f16d
          History

          Inflammation,Blood brain barrier,Wip1,Lipopolysaccharide,Sonic hedgehog signaling

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