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July 23, 2025, 03:19

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In this commentary, we discuss the recent work by He et al. published in the World Journal of Gastroenterology, which identifies translocator protein (TSPO) as a novel player in the immunopathogenesis of inflammatory bowel disease (IBD), with a particular focus on neutrophil-driven ROS production and NET formation. The study highlights elevated TSPO expression in both the gut and peripheral neutrophils of IBD patients and further correlates this with increased neuroinflammatory signals in the brains of colitic mice. We commend the authors for linking gut and brain inflammation via TSPO, a mitochondrial protein long implicated in innate immune regulation. However, we offer several points for deeper consideration. Prior studies have shown that TSPO knockout in mice worsens DSS-induced colitis by enhancing macrophage pyroptosis, suggesting that TSPO may have cell-type–dependent functions. This contrasts with He et al.'s findings that TSPO antagonism reduces neutrophil ROS and NETs, raising questions about the net effects of modulating TSPO. We propose that future studies adopt cell-specific knockout models to clarify these roles. Additionally, we address the translational relevance of TSPO imaging in the CNS. In rodents, TSPO is upregulated in activated microglia; however, human data suggest that TSPO levels correlate more with immune cell density than activation state. This distinction is crucial when interpreting PET signals in IBD-associated brain inflammation. Moreover, astrocytic TSPO expression may contribute to these findings and deserves further discussion. We also suggest validating the current results in larger human cohorts, including through single-cell RNA sequencing and TSPO-PET studies. Investigating the behavioral and cognitive consequences of colitis-induced brain TSPO changes would further elucidate the gut-brain inflammatory axis. Finally, given the contradictory effects of different TSPO ligands (e.g., PK11195 vs. flunitrazepam), a pharmacological exploration of TSPO modulators with improved selectivity and safety is warranted. In conclusion, this letter supports the innovative perspective introduced by He et al., while also emphasizing the complexity of TSPO’s role across immune cell types and organ systems. A more nuanced understanding of TSPO biology may yield novel insights into both intestinal and neuroimmune pathologies.

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