Abstract Background and Goal Septic encephalopathy (SE) is closely associated with disruption of blood brain barrier (BBB), resulting in neurological deficits and poor clinical outcomes. Protein tyrosine phosphatase receptor type O (PTPRO)regulates disease states by dephosphorylating membrane-associated proteins and modulating intracellular signaling. The purpose of this study was to examine the role of PTPRO in regulating BBB permeability and to assess the therapeutic potential of Pi, a novel PTPRO inhibitor, in mitigating BBB disruption in SE. Experimental Approach Genetic (PTPRO overexpression and knockout) and pharmacological (Pi treatment) interventions were used to assess the functional effect of PTPRO on BBB permeability in cerebral endothelial cells and a murine SE model. Changes in cytoskeletal organization and intercellular gap formation were examined by immunofluorescence experiment. Key Results LPS challenge upregulated PTPRO expression in both SE brain tissues and cerebral endothelial cells. LPS-induced PTPRO elevation triggered actin polymerization, stress fiber formation, and intercellular gaps, which can be abolished by Pi or PTPRO silencing RNA. PTPRO overexpression exacerbated these changes, while Pi treatment reversed thrombin-induced permeability in bEND.3 cells and primary endothelial cells isolated from PTPRO-/- mice. Mechanistically, PTPRO regulates cytoskeletal dynamics via the ErbB2-Rho-MLC2 pathway. PTPRO knockout mice and Pi-treated mice exhibited diminished disruption of BBB permeability, with limited effects on inflammatory cytokines in SE. Conclusion and Implications These findings establish PTPRO as a critical therapeutic target in sepsis-induced BBB disruption. Pi’s efficacy suggests a novel therapeutic avenue to preserve BBB integrity and mitigate SE progression, warranting further pharmacological exploration in sepsis management. This abstract is funded by: National Natural Science Foundation of China (82071849), the Natural Science Foundation of Anhui Province (Grant No. 2408085MH234), The 2024 Open Project of Anhui Province Key Laboratory of Basic and Translational Research of Inflammation-related Diseases (Grant No. YZ2024D07), Special Program for Key Supported and Emerging Disciplines of Bengbu Medical University(Grant No. 2024bypy012)
Wu et al. (Fri,) studied this question.