Christine Haarslev
2026
Harnessing anti-TNFR1 therapy has a limited impact on inflammation and motor function
after stroke in obese male mice
Abstract
Obesity is a significant global health concern that exacerbates the risk and severity of
ischemic stroke through chronic low-grade systemic inflammation and metabolic
dysregulation. Tumor necrosis factor (TNF) signaling, particularly through its TNF receptor 1
(TNFR1), is involved in obesity-driven inflammation and adverse stroke outcomes. To assess
the potential of TNFR1 blockade as a treatment strategy, we employed a diet-induced obesity
model of ischemic stroke. Male C57BL/6 mice were fed a regular diet or high-fat diet for 6
weeks prior to stroke induction via photothrombosis and treated with either a TNFR1neutralizing antibody or isotype control antibody. Outcomes were evaluated using motor
function assessments, systemic inflammatory biomarker measurements, and brain tissue
analysis, including evaluation of microglia, astrocytes, oligodendrocytes, myelin integrity, and
stroke size. Results showed that obese mice exhibited worsened motor deficits and
heightened systemic inflammation following stroke compared to non-obese controls.
Treatment with anti-TNFR1 antibody did not ameliorate the increased functional deficits but
did improve interleukin-6 cytokines levels after stroke in obese mice, while it had no eOects
on non-obese controls. Moreover, anti-TNFR1 therapy did not impact infarct size, microglial
and astrocyte reactivity, or myelin integrity in both dietary groups. Overall, TNFR1-targeted
therapy had a limited impact on obesity-exacerbated stroke outcomes, suggesting the need to
explore broader or combination immunomodulatory approaches. These findings also
emphasize the importance of considering comorbidities such as obesity in stroke, as they can
influence both disease progression and treatment eOectiveness.