Il-6 knockout reduces doxorubicin-induced toxicity in the developing mouse brain

Jonas Yeung; Henry Quach; Amy P Wong; Anne L Wheeler; Rosanna Weksberg; Sharon L Guger; Russell J Schachar; Shinya Ito; Johann Hitzler; Brian J Nieman

doi:10.1016/j.bbi.2025.06.034

Il-6 knockout reduces doxorubicin-induced toxicity in the developing mouse brain

Brain Behav Immun. 2025 Oct:129:609-619. doi: 10.1016/j.bbi.2025.06.034. Epub 2025 Jun 28.

Authors

Affiliations

¹ Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada; Translational Medicine, Hospital for Sick Children Research Institute, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada. Electronic address: jonas.yeung@sickkids.ca.
² Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.
³ Neuroscience and Mental Health, Hospital for Sick Children Research Institute, Toronto, ON, Canada; Department of Physiology, University of Toronto, Toronto, ON, Canada.
⁴ Department of Pediatrics, University of Toronto, Toronto, ON, Canada; Institutes of Medical Science, University of Toronto, Toronto, ON, Canada.
⁵ Department of Psychology, Hospital for Sick Children, Toronto, ON, Canada.
⁶ Neuroscience and Mental Health, Hospital for Sick Children Research Institute, Toronto, ON, Canada; Institutes of Medical Science, University of Toronto, Toronto, ON, Canada; Department of Psychiatry (Emeritus), University of Toronto, ON, Canada.
⁷ Translational Medicine, Hospital for Sick Children Research Institute, Toronto, ON, Canada; Clinical Pharmacology and Toxicology, Hospital for Sick Children, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
⁸ Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada; Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada.
⁹ Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada; Translational Medicine, Hospital for Sick Children Research Institute, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Ontario Institute for Cancer Research, ON, Canada.

PMID: 40588079
DOI: 10.1016/j.bbi.2025.06.034

Abstract

Purpose: Doxorubicin (DXR) treatment is linked to cognitive impairments in cancer patients, including pediatric survivors. However, since DXR does not readily cross the blood-brain barrier, systemic mechanisms such as DXR-induced elevations of pro-inflammatory cytokines may be key in mediating neurotoxicity. Using a mouse model of pediatric cancer treatment, we investigated cytokine levels following DXR treatment and evaluated its effects on brain toxicity through genetic knockout.

Experimental design: Mice were treated with DXR at a childhood-equivalent age (P17 and P19) and sacrificed at P20 to measure cytokine levels in plasma and brain tissue. IL-6 was significantly elevated in both after DXR treatment. We assessed brain volume alterations using longitudinal in vivo MRI (from P14 to P98) and performed histological analysis to further explore DXR impact on the brain in wildtype and Il-6 knockout mice.

Results: DXR treatment caused widespread brain volume reductions. The volume reductions were partially rescued in Il-6 knockout mice treated with DXR, which showed progressive brain volume improvements over time. Additionally, histological analysis revealed an increase in the pro-inflammatory microglial marker CD68 in wildtype mice treated with DXR, a response that was mitigated in Il-6 knockout mice.

Conclusions: Our results indicate that IL-6 plays a role in DXR-induced brain toxicity, offering a potential mechanism by which DXR affects the brain despite its limited penetration of the blood-brain barrier. This study also provides evidence that targeting IL-6 may alleviate side effects of chemotherapy associated with structural brain changes, such as cognitive deficits in cancer survivors treated with DXR.

Keywords: Cancer survivorship; Cytokines; Doxorubicin; Histology; Inflammation; Late effects; MRI; Mouse model; Neuroanatomy; Structure.

MeSH terms

Animals
Antibiotics, Antineoplastic / toxicity
Blood-Brain Barrier / metabolism
Brain* / drug effects
Brain* / growth & development
Brain* / metabolism
Brain* / pathology
Cytokines / metabolism
Doxorubicin* / pharmacology
Doxorubicin* / toxicity
Female
Interleukin-6* / genetics
Interleukin-6* / metabolism
Magnetic Resonance Imaging
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Microglia / metabolism

Substances

Doxorubicin
Interleukin-6
interleukin-6, mouse
Antibiotics, Antineoplastic
Cytokines