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

被引：0

作者：

Yeung, Jonas ^{[1
,2
,3
]}

Quach, Henry ^{[4
,5
]}

Wong, Amy P. ^{[4
,5
]}

Wheeler, Anne L. ^{[6
,7
]}

Weksberg, Rosanna ^{[8
,9
]}

Guger, Sharon L. ^{[10
]}

Schachar, Russell J. ^{[6
,9
,11
]}

Ito, Shinya ^{[2
,12
,13
]}

Hitzler, Johann ^{[4
,8
,14
]}

Nieman, Brian J. ^{[1
,2
,3
,15
]}

机构：

[1] Hosp Sick Children, Mouse Imaging Ctr, 25 Orde St, Toronto, ON M5T 3H7, Canada

[2] Hosp Sick Children, Translat Med, Res Inst, Toronto, ON, Canada

[3] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada

[4] Hosp Sick Children, Dev & Stem Cell Biol, Toronto, ON, Canada

[5] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada

[6] Hosp Sick Children, Neurosci & Mental Hlth, Res Inst, Toronto, ON, Canada

[7] Univ Toronto, Dept Physiol, Toronto, ON, Canada

[8] Univ Toronto, Dept Pediat, Toronto, ON, Canada

[9] Univ Toronto, Inst Med Sci, Toronto, ON, Canada

[10] Hosp Sick Children, Dept Psychol, Toronto, ON, Canada

[11] Univ Toronto, Dept Psychiat, Toronto, ON, Canada

[12] Hosp Sick Children, Clin Pharmacol & Toxicol, Toronto, ON, Canada

[13] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON, Canada

[14] Hosp Sick Children, Div Haematol Oncol, Toronto, ON, Canada

[15] Ontario Inst Canc Res, Toronto, ON, Canada

来源：

BRAIN BEHAVIOR AND IMMUNITY | 2025年 / 129卷

基金：

加拿大健康研究院;

关键词：

MRI; Structure; Neuroanatomy; Late effects; Cancer survivorship; Mouse model; Doxorubicin; Cytokines; Inflammation; Histology; ACUTE LYMPHOBLASTIC-LEUKEMIA; LONG-TERM SURVIVORS; CANCER SURVIVORS; COGNITIVE IMPAIRMENT; ADULT SURVIVORS; IN-VIVO; INTERLEUKIN-6; INFLAMMATION; CHEMOTHERAPY; VOLUMES;

D O I：

10.1016/j.bbi.2025.06.034

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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 DXRinduced 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.

引用

页码：609 / 619

页数：11

共 85 条

[1] Doxorubicin impairs cognitive function by upregulating AMPAR and NMDAR subunit expression and increasing neuroinflammation, oxidative stress, and apoptosis in the brain [J].