The Role of CCL11-CCR3 Induced Mitochondrial Dysfunction and Oxidative Stress in Cognitive Impairment in Early-onset Schizophrenia: Insights from Preclinical Studies.

Abstract

Abnormal cytokine expression has been implicated as a potential contributor to neurodegeneration. This study aimed to investigate the plasma cytokine profiles in patients with early-onset schizophrenia (SCZ) and to explore the molecular mechanisms underlying the role of the key cytokine CCL11 in contributing to cognitive impairment. Plasma concentrations of 44 cytokines were quantified in individuals with SCZ. The effects of CCL11 on mitochondrial function were examined in vitro using primary hippocampal neurons. An in vivo model was subsequently developed by administering CCL11 into the lateral ventricle. The impact of the CCL11-CCR3 signaling pathway on mitochondrial function, oxidative stress, and cognitive function within the hippocampus was assessed using a combination of behavioral testing, molecular biology experiments, transcriptomic analysis, and non-targeted metabolomics. In individuals with SCZ, CCL11 and IL-13 levels were notably higher than in controls. In vitro, CCL11 exposure caused mitochondrial dysfunction and increased reactive oxygen species in hippocampal neurons. In vivo, CCL11-treated mice showed cognitive deficits, mitochondrial fission, and neuroinflammation in the hippocampus. Comprehensive integration of transcriptomic and metabolomic data revealed that CCL11 significantly disrupted the Glucokinase/Glucose-6-phosphate metabolism pathway, coinciding with elevated metabolites indicative of oxidative damage. Finally, downregulation of the CCR3 receptor in the hippocampus mitigated CCL11-induced oxidative stress, mitochondrial dysfunction, and cognitive impairment. CCL11 causes cytotoxicity in neurons by increasing oxidative stress and mitochondrial dysfunction. In a mouse model, knockout of the CCR3 receptor alleviates CCL11-induced cognitive impairment, mitochondrial dysfunction, and oxidative stress.