Ultrasound Mediated Mild Hyperthermia Resolves Neuroinflammation in an Animal Model
Date
2024-11-01
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Abstract
Chronic neuroinflammation is an often overlooked aspect of the development of neurodegenerative and autoimmune disease, especially in older populations, and there are few treatments capable of addressing this type of inflammation. We sought to address this gap by following up on our clinical finding where focused ultrasound resolved chronic radiation-related neuroinflammation Using ultrasound-mediated mild hyperthermia to treat chronic neuroinflammation in a preclinical mouse model, we investigated the impact on the immune response, and the resolution of inflammation. Seven days after peripheral infection, we targeted the mouse midbrain with focal hyperthermia (4 mins at 39 oC and 6 mins at 42 oC). Proteomic changes were analyzed, and demonstrated that hyperthermia reduced inflammation in female mice 24 hours after treatment, alleviating blood brain barrier disruption, antigen presentation, and anti-viral signalling. In contrast, male mice did not show a change in inflammatory mediators at 24 hours, but showed an upregulation in proteins associated with the heat shock response, chromatin maintenance, and chaperone mediated autophagy. At the cellular level, microglia and astrocytes demonstrated homeostatic phenotypes seven days after hyperthermia treatment in both males and females. We also investigated the role of the immunosuppressive CD200/CD200R signalling pathway in immune resolution, and discovered that it is dysregulated in chronic neuroinflammation – exacerbating inflammation in males, while maintaining a resolving function in females. Ultrasound mediated mild hyperthermia was able to restore homeostatic CD200/CD200R signalling, alleviating the pro-inflammatory rewiring observed in males. Consequently, we demonstrate that ultrasound mediated mild hyperthermia is capable of restoring the homeostatic function of receptors, and resolving chronic neuroinflammation across pathology, through the induction of the heat shock response. We propose a new application of clinically approved magnetic resonance guided focused ultrasound systems in the treatment of chronic neuroinflammation, with the potential for rapid clinical translation.
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Keywords
Heat shock response, CD200R, Inflammation, Ultrasound, Sex differences, Hyperthermia
Citation
Seasons, G. (2024). Ultrasound mediated mild hyperthermia resolves neuroinflammation in an animal model (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.