Repeated Low-Level Inflammatory Challenge Leads to Alterations in the TNF-CXCL10 Signalling Pathway in Mouse Cerebral...

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Chronic systemic inflammation is linked to cerebral endothelial dysfunction and neurological disorders.
• Endothelial inflammatory signaling is a key process in this context.
• The precise mechanisms remain unclear.

Purpose of the Study:

• To investigate the role of the Tumour Necrosis Factor-C-X-C Motif Chemokine Ligand 10 (TNF-CXCL10) pathway in cerebral endothelial cells under repeated low-level inflammation.
• To analyze the effects on endothelial cell activation and function.
• To identify potential therapeutic targets for neurovascular diseases.

Main Methods:

• Transcriptomic analysis of RNASeq datasets.
• Exposure of mouse cerebral endothelial cells (bEnd.3) to repeated low-level Tumour Necrosis Factor (TNF) or control.
• Analysis of gene and protein expression (ICAM1, CXCL10, STAT1, TRAF2, IFNγ) via qRT-PCR and western blotting.
• Assessment of endothelial cell proliferation, apoptosis, and CXCL10 knockdown effects.

Main Results:

• Repeated TNF exposure significantly upregulated Intercellular Adhesion Molecule 1 (ICAM1) and CXCL10 mRNA and protein levels.
• Increased Signal transducer and activator of transcription 1 (STAT1) and phosphorylated-STAT1 (pSTAT1) protein levels were observed.
• Endothelial cell proliferation and apoptosis significantly increased with repeated TNF exposure.
• CXCL10 knockdown reduced TNF-induced caspase 3/7 activity.

Conclusions:

• Low-level repetitive inflammation upregulates the TNF-CXCL10 pathway in mouse cerebral endothelial cells.
• Modulation of the TNF-CXCL10 pathway influences endothelial cell behavior.
• Targeting this pathway may offer a therapeutic strategy for neurovascular disorders.