IL-4Rα signalling influences behavioural and immune responses in Trypanosoma brucei-infected mice: Evidence for iloprost as a neuroprotective agent

This study investigated the effects of Trypanosoma brucei infection on neuroinflammation, immune response, and behaviour in both wild-type (WT) and IL-4Rα inhibited (IL-4Rα┴) mice. To achieve this, 9-week-old WT and IL-4Rα┴ mice were infected with T. brucei intraperitoneally (5 ×10² parasites) and the treated groups received 200 μg/kg/day of Iloprost intraperitoneally. Results from infected animals showed that behavioural activity and inflammation were reduced in animals treated with Iloprost. Euthanasia was performed on 12 days post-infection (dpi), and prefrontal cortex (PFC), Hippocampus (HPC) and blood were collected. PCR confirmed the presence of T. brucei in the brain and blood, demonstrating its ability to cross the blood-brain barrier. CXCL10, a key chemokine implicated in neuroinflammation, was elevated in infected mice, particularly in IL-4Rα┴ mice, which lack the ability to initiate protective type 2 immune responses. Treatment with Iloprost suppressed CXCL10 expression and reduced inflammation. Behavioural assessments revealed that T. brucei infection induced anxiety-like behaviours and hypoactivity. Interestingly, IL-4Rα inhibition appeared to reduce anxiety-like behaviours in infected mice, while Iloprost treatment had an anxiolytic effect. Locomotor deficits were observed in infected mice, with IL-4Rα┴ mice showing more pronounced hypoactivity. However, both Iloprost and Diminazine improved locomotor activity. At the molecular level, IL-4Rα inhibition resulted in upregulation of pro-inflammatory cytokines such as TNF-α and elevated nitric oxide levels, contributing to CNS inflammation. Iloprost treatment reduced these markers and supported anti-inflammatory pathways. These findings highlight the complex interplay between immune regulation, neuroinflammation, and behaviour in trypanosome infection, with IL-4Rα signalling playing a critical role in modulating disease outcomes. Therapeutic interventions targeting these pathways, such as Iloprost, may offer neuroprotective benefits in African trypanosomiasis.