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SHP-1 suppresses endotoxin-induced uveitis by inhibiting the TAK1/JNK pathway |
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| Authors: | Xiaonan Zhuang Jun Ma Sisi Xu Zhongcui Sun Rong Zhang Meng Zhang Gezhi Xu |
| Institution: | 1. Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China
Contribution: Conceptualization (lead), Data curation (lead), Formal analysis (lead), ?Investigation (lead), Methodology (lead), Writing - original draft (lead), Writing - review & editing (lead);2. Eye Institute, Eye & ENT Hospital, Fudan University, Shanghai, China Contribution: Data curation (lead), ?Investigation (lead), Resources (equal), Writing - original draft (equal), Writing - review & editing (lead);3. Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China Contribution: Data curation (equal), ?Investigation (lead), Methodology (lead);4. Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China Contribution: Formal analysis (equal), ?Investigation (equal), Methodology (equal), Resources (equal), Validation (equal);5. Eye Institute, Eye & ENT Hospital, Fudan University, Shanghai, China Contribution: ?Investigation (equal), Methodology (equal);6. Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China Contribution: ?Investigation (equal), Methodology (equal);7. Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China |
| Abstract: | We investigated how Src-homology 2-domain phosphatase-1 (SHP-1) regulates the inflammatory response in endotoxin-induced uveitis (EIU), and the signalling pathways involved. One week after intravitreal injection of short hairpin RNA targeting SHP-1 or SHP-1 overexpression lentivirus in rats, we induced ocular inflammation with an intravitreal injection of lipopolysaccharide (LPS). We then assessed the extent of inflammation and performed full-field electroretinography. The concentrations and retinal expression of various inflammatory mediators were examined with enzyme-linked immunosorbent assays and Western blotting, respectively. SHP-1 overexpression and knockdown were induced in Müller cells to study the role of SHP-1 in the LPS-induced inflammatory response in vitro. Retinal SHP-1 expression was up-regulated by LPS. SHP-1 knockdown exacerbated LPS-induced retinal dysfunction and increased the levels of proinflammatory mediators in the retina, which was abrogated by a c-Jun N-terminal kinase (JNK) inhibitor (SP600125). SHP-1 overexpression had the opposite effects. In Müller cells, the LPS-induced inflammatory response was enhanced by SHP-1 knockdown and suppressed by SHP-1 overexpression. SHP-1 negatively regulated the activation of the transforming growth factor-β-activated kinase-1 (TAK1)/JNK pathway, but not the nuclear factor-κB pathway. These results indicate that SHP-1 represses EIU, at least in part, by inhibiting the TAK1/JNK pathway and suggest that SHP-1 is a potential therapeutic target for uveitis. |
| Keywords: | inflammation JNK LPS Müller cells SHP-1 |