DOI: 10.1177/15230864261464407 ISSN: 1523-0864

Inflammation Impairs Poststroke Recovery by Disrupting Iron Homeostasis in Brain

Xin Guo, Xiaofang Jin, Shaomeng Kang, Yingying Han, Qiaoya Zhao, Lihui Wu, Xintong Shi, Jingsi Meng, Peng Yu, Guofen Gao, Fudi Wang, Kang Han, Yan-Zhong Chang
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Aim:

The activation of microglia triggers an inflammatory response, which is frequently associated with an imbalance of iron metabolism. This study aimed to determine whether inflammation-associated iron dyshomeostasis contributes to impaired poststroke recovery and to explore the underlying mechanisms.

Results:

Ferroportin 1 (FPN1) deficiency in neurons and glial cells delayed sensorimotor function recovery following cerebral ischemia. FPN1 deficiency was associated with aggravated neuronal injury, enhanced apoptosis- and necroptosis-associated signaling, impaired myelin- and synapse-related repair, and reduced dendritic spine density in the ischemic cortex. Histological analyses, including hematoxylin and eosin staining and Nissl staining, further supported more severe peri-infarct pathological damage in Fpn1 Nestin -CKO mice. In addition, increased IgG extravasation indicated aggravated blood–brain barrier (BBB) disruption and secondary neurovascular injury after stroke. These pathological changes were accompanied by increased iron accumulation in the ischemic cortex and altered expression of iron metabolism-related molecules. Elevated inflammatory cytokine expression and increased hepcidin levels were associated with disrupted brain iron homeostasis in Fpn1 Nestin -CKO mice. Inhibition of JAK-STAT signaling with AG490 reduced p-STAT3 and hepcidin levels and was associated with modulation of iron-related and repair-associated responses, with more pronounced effects observed in Fpn1 -deficient mice.

Innovation and Conclusion:

These findings highlight a close association between inflammatory signaling, BBB dysfunction, and iron dyshomeostasis during poststroke recovery. Our results suggest that delayed sensorimotor recovery in mice with neuronal and glial FPN1 deficiency may be linked to inflammation-associated BBB disruption and subsequent iron accumulation in the ischemic brain. Antioxid. Redox Signal. 00, 000–000.

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