Systemic inhibition of soluble TNF significantly changes glial cell populations leading to improved myelin integrity and better functional outcome after experimental stroke

Tumor necrosis factor (TNF) is highly upregulated after ischemic stroke and plays a crucial role in shaping the neuroinflammatory response that follows. Therapies aimed at inhibiting detrimental soluble (sol)TNF-TNF receptor 1 (TNFR1) signaling are gaining interest as new treatment options for neuroinflammatory conditions. We previously demonstrated that XPro1595, a selective solTNF inhibitor, decreased inflammation and improved functional outcome in the acute phase of experimental stroke. Here, we extended these studies by investigating the effects of solTNF inhibition on inflammation, functional outcome, and cognitive impairments in the subacute phases after stroke onset. We observed that in mice treated with XPro1595, glial cell responses were altered 7 and 14 days after experimental stroke, with changes in microglial morphology, as well as astrocyte and oligodendrocyte cell populations, pointing to altered reactive states. While the number of pre-myelinating oligodendrocytes was decreased in the ipsilateral cortex, XPro1595 upregulated oligodendrocyte lipid levels and improved myelin integrity. Similarly, the number of astrocytes in the ipsilateral cortex was decreased with XPro1595 treatment, followed by changes to their lipid profile. Moreover, the treatment led to a decrease in systemic immune cell numbers, indicative of a dampened peripheral inflammatory response. These changes were followed by increased hippocampal pro-brain-derived neurotrophic factor levels and an improvement in cognitive function, seen as better recognition memory, as well as improved motor asymmetry. In conclusion, these findings support a long-term protective effect of inhibiting solTNF in experimental ischemic stroke.