Interleukin-33 (IL-33) is increasingly being recognized as a key immunomodulatory cytokine in many neurological diseases. In the present study, wild-type (WT) and IL-33−/− mice received intracerebroventricular (i.c.v.) injection of lipopolysaccharide (LPS) to induce neuroinflammation. Intravital microscopy was employed to examine leukocyte–endothelial interactions in the brain vasculature. The degree of neutrophil infiltration was determined by myeloperoxidase (MPO) staining. Real-time PCR and western blotting were used to detect endothelial activation. Enzyme-linked immunosorbent assay and quantitative PCR were conducted to detect pro-inflammatory cytokine levels in the brain. In IL-33−/− mice, neutrophil infiltration in the brain cortex and leukocyte–endothelial cell interactions in the cerebral microvessels were significantly decreased as compared to WT mice after LPS injection. In addition, IL-33−/− mice showed reduced activation of microglia and cerebral endothelial cells. In vitro results indicated that IL-33 directly activated cerebral endothelial cells and promoted pro-inflammatory cytokine production in LPS-stimulated microglia. Our study indicated that IL-33/ST2 signaling plays an important role in the activation of microglia and cerebral endothelial cells and, therefore, is essential in leukocyte recruitment in brain inflammation. The role of IL-33/ST2 in LPS induced neuroinflammation

Septic encephalopathy (SE) represents a severe inflammatory syndrome linked to elevated septic mortality rates, lacking specific therapeutic interventions, and often resulting in enduring neurological sequelae. The present investigation endeavors to elucidate the involvement of C-X-C Motif Chemokine Receptor 2 (CXCR2) in the pathogenesis of SE and to explore the potential of CXCR2 modulation as a therapeutic avenue for SE. Employing a murine SE model induced by lipopolysaccharide (LPS) administration, CXCR2 knockout mice and the CXCR2 inhibitor SB225002 were utilized to assess neutrophil recruitment, endothelial integrity, and transendothelial migration. Our findings substantiate that either CXCR2 deficiency or its inhibition curtails neutrophil recruitment without impacting their adhesion to cerebral endothelial cells. This phenomenon is contingent upon endothelial CXCR2 expression rather than CXCR2’s presence on neutrophils. Furthermore, the CXCR2 blockade preserves the integrity of tight junction protein ZO-1 and mitigates F-actin stress fiber formation in cerebral endothelial cells following septic challenge. Mechanistically, CXCL1-mediated CXCR2 activation triggers cerebral endothelial actin contraction via Rho signaling, thereby facilitating neutrophil transmigration in SE. These observations advocate for the potential therapeutic efficacy of CXCR2 inhibition in managing SE.

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.

Background/Objectives: Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), remains a major global health problem. Drug resistance and the limitations of sputum-based diagnostic methods highlight the need for additional host-response biomarkers. Protein tyrosine phosphatase receptor type O (PTPRO) has been implicated in inflammatory signaling and macrophage immune regulation, but its relationship with TB-related host transcriptional responses remains unclear. This study aimed to identify and preliminarily evaluate a PTPRO-related blood transcriptional signature with potential relevance to TB discrimination and treatment-response assessment. Methods: Genes correlated with PTPRO expression were first screened using TCGA-LUSC as a large human transcriptomic discovery resource. The resulting candidate genes were then filtered in TB-related whole-blood datasets by intersecting genes upregulated in TB compared with healthy controls, pneumonia, and lung cancer. This strategy yielded a five-gene PTPRO-related signature, termed PO5. The signature was evaluated in independent GEO cohorts and further explored by RT-qPCR in H37Ra-infected THP-1-derived macrophages and in a small clinical blood cohort. A PO5-derived TB risk score was calculated for each sample, and receiver operating characteristic analysis was used to assess discriminatory performance. Changes in TB risk scores during anti-TB treatment were also examined. Results: PTPRO expression was increased in TB whole-blood transcriptomic data and in H37Ra-infected macrophages. In public datasets, PO5 showed potential for distinguishing TB from healthy controls, latent TB, pneumonia, and lung cancer. PO5-derived TB risk scores also decreased after anti-TB treatment. In the exploratory clinical cohort, several PO5 genes showed expression changes in the same general direction as those observed in the public datasets, although the small sample size limited the strength of this evidence. Conclusions: PO5 represents a preliminary PTPRO-related blood transcriptional signature with potential relevance to TB discrimination and treatment-response assessment. These findings remain exploratory and require validation in larger prospective multicenter cohorts, together with further mechanistic studies.