Brain endothelial PTPRO drives LPS-induced metabolic reprogramming and neuroinflammation in sepsis-associated encephalopathy

Abstract

Background: Sepsis-associated encephalopathy (SAE) is characterized by profound neuroinflammation and blood–brain barrier (BBB) disruption, yet the molecular mechanisms linking endothelial metabolic reprogramming to neuroinflammatory responses remain poorly defined. Protein tyrosine phosphatase receptor type O (PTPRO) has been implicated in endothelial signaling; however, its role in metabolic and inflammatory dysregulation during SAE is unknown.

Methods: We analyzed transcriptomic responses to lipopolysaccharide (LPS) challenge in control and PTPRO-silenced brain microvascular endothelial bEND.3 cells to define the impact of PTPRO on endothelial gene expression under septic stress. Endothelial cells with PTPRO overexpression, siRNA-mediated knockdown, or pharmacologic inhibition were assessed for glycolytic activity, glucose uptake, HIF-1α signaling, BBB integrity, and inflammatory responses following LPS exposure. LPS-induced neuroinflammation models were established in wild-type, systemic PTPRO knockout (PTPRO⁻/⁻), and endothelial-specific PTPRO conditional knockout (E-cKO) mice, and disease severity was systematically evaluated.

Results: We provide the first evidence that PTPRO regulates LPS-induced glycolytic pathways at the transcriptomic level. PTPRO silencing or inhibition in bEND.3 cells significantly attenuated LPS-induced glycolytic activation, HIF-1α accumulation, glucose transporter translocation, and lactate production. In vivo, LPS-induced neuroinflammation was associated with enhanced glycolysis, increased HIF-1α expression, BBB disruption, and elevated neuroinflammatory cytokine production; these effects were markedly reduced in both systemic and conditional endothelial-specific PTPRO-deficient mice, with preservation of BBB integrity and decreased neutrophil infiltration. Mechanistically, PTPRO modulated ErbB2 phosphorylation at multiple tyrosine residues and activated AKT–mTOR signaling under inflammatory conditions, linking PTPRO to endothelial glycolytic reprogramming and inflammatory activation. Pharmacologic inhibition of HIF-1α or glycolysis suppressed pro-inflammatory cytokine production, indicating that PTPRO promotes endothelial inflammation through a HIF-1α–dependent glycolytic pathway.

Conclusions: PTPRO drives endothelial glycolytic reprogramming and neuroinflammation in LPS-induced neuroinflammation by regulating HIF-1α signaling through the ErbB2–AKT–mTOR axis. Targeting PTPRO confers metabolic, neurovascular, and anti-inflammatory protection, highlighting PTPRO as a promising therapeutic target for SAE.

Graphical abstract:

Supplementary Information: The online version contains supplementary material available at 10.1186/s12974-026-03790-7.

Keywords: Blood-brain barrier; Brain endothelial cells; Glycolysis; HIF-1α; Neuroinflammation; PTPRO; Sepsis-associated encephalopathy.