Interleukin‐6 induces cognitive impairment via toll‐like receptor 4 (TLR4)‐mediated neuroinflammation and neurodegeneration in mice with chronic kidney disease

Past epidemiological and experimental studies in rodents have demonstrated that chronic kidney disease (CKD) leads to cognitive impairment. However, the underlying mechanism requires further investigation. Herein, a mouse model of CKD was established using conventional 5/6 nephrectomy. We aimed to examine the relationship between CKD and cognitive impairment and elucidate the underlying mechanisms. Cognitive behavior was assessed using the Morris water maze, novel object recognition test, and fear conditioning test. Further experiments were also conducted to investigate the underlying molecular mechanisms. Our clinical data revealed a decrease in cognitive function among patients with CKD, accompanied by elevated plasma levels of pro‐inflammatory cytokines. A positive correlation between cytokine concentrations and serum creatinine levels, as well as a significant positive correlation with cognitive dysfunction, were observed. Correlation analyzes demonstrated that hippocampal cytokine levels were positively correlated with serum creatinine levels and cognitive dysfunction in CKD model mice. Furthermore, 20 mg/mL interleukin‐6 (IL‐6) significantly decreased HT22 cell activity in vitro. Further, HT22 cells treated with IL‐6 showed increased expression levels of toll‐like receptor 4 (TLR4) and myeloid differentiation primary response gene 88 (MyD88), thereby inducing the nuclear factor kappa‐B p65 inflammatory pathway and mitochondria‐dependent apoptosis. The CKD mouse model showed increased expression of TLR4 and cytokines in the hippocampus. TLR4knockdown antagonized the IL‐6‐mediated pro‐inflammatory and pro‐apoptotic effects in HT22 cells. TLR4knockdown in the CKD model mice decreased hippocampal inflammation and increased the number of neuron dendrites, thus ameliorated cognitive impairment. These results suggest that IL‐6 triggers TLR4 activation to induce neuroinflammation and neurodegeneration in CKD, ultimately culminate in cognitive impairment. Diagrammatic representation of the role of IL‐6/TLR4 between CKD and cognitive impairment. CKD patients suffer fromimpaired renal function, accompanied by inflammatory reactions in the body, and simultaneous increased levels of inflammatory factors in the brain, especially IL‐6. This triggers overactivation of the TLR4/MyD88 pathway, increasing the expression of p65 and CL‐Casp3, and thus promoting neuroinflammation and neurodegeneration leading to cognitive dysfunction. CKD, chronic kidney disease; IL, interleukin; TLR4, Toll‐like receptor 4. Chronic kidney disease (CKD) leads to cognitive impairment, with elevated levels of pro‐inflammatory cytokines such as interleukin‐6 (IL‐6) playing a significant role.IL‐6 was shown to activate the toll‐like receptor 4 (TLR4)/myeloid differentiation factor 88/nuclear factor kappa B inflammatory pathway, resulting in increased apoptosis and inflammation in neurons.TLR4knockdown in a CKD mouse model reduced neuroinflammation, and improved cognitive function. Chronic kidney disease (CKD) leads to cognitive impairment, with elevated levels of pro‐inflammatory cytokines such as interleukin‐6 (IL‐6) playing a significant role. IL‐6 was shown to activate the toll‐like receptor 4 (TLR4)/myeloid differentiation factor 88/nuclear factor kappa B inflammatory pathway, resulting in increased apoptosis and inflammation in neurons. TLR4knockdown in a CKD mouse model reduced neuroinflammation, and improved cognitive function.