Translocator protein facilitates neutrophil-mediated mucosal inflammation in inflammatory bowel diseases

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic gastrointestinal disorders with an increasing global prevalence and significant healthcare impact. The exact etiology of this condition remains unclear. Neutrophils play a critical role in IBD pathogenesis. Translocator protein (TSPO), a mitochondrial protein linked to immune responses, has demonstrated potential as an inflammatory marker. However, its role in IBD remains underexplored.

To investigate the role of TSPO in IBD pathogenesis, particularly in neutrophils.

Bioinformatics analyses of Gene Expression Omnibus datasets (GE75214, GSE94648, GSE156776) assessed TSPO expression in IBD patients. TSPO expression was evaluated in human IBD samples, neutrophiles and a chronic colitis mouse model. Neutrophil function was examined in 18 samples using reactive oxygen species (ROS) production and neutrophil extracellular trap (NET) formation assays. Positron emission tomography-computed tomography (PET-CT) imaging and histology from 12 mice revealed TSPO expression in colitis. PET-CT and immunofluorescence staining assessed TSPO expression in brain under neuroinflammation condition.

Bioinformatics analysis revealed elevated TSPO expression in the intestinal mucosa and peripheral blood of patients with IBD, especially in neutrophils. This was confirmed by quantitative real-time polymerase chain reaction and immunohistochemical staining, which showed a significant upregulation of TSPO in active IBD. Neutrophils from patients with UC and CD exhibited higher TSPO expression, which correlated with increased ROS production and NET formation. In a mouse model of dextran sodium sulfate-induced chronic colitis, TSPO was upregulated in the colonic neutrophils and brain tissues, indicating its systemic involvement. PET-CT imaging showed enhanced TSPO uptake in the inflamed colon and brain regions, particularly in the microglia, highlighting neuroinflammation.

TSPO is significantly upregulated in neutrophils in IBD and contributes to intestinal inflammation. Its elevated expression in gut highlights its potential as a promising therapeutic target for IBD.