LCN2 induces neuronal loss and facilitates sepsis-associated cognitive impairments
Abstract Sepsis-associated encephalopathy (SAE) is a severe neurological syndrome marked by widespread brain dysfunctions due to sepsis. Despite increasing data supporting the hypothesis of neuronal damage, the exact mechanism of sepsis-related cognitive disorders and therapeutic strategies remain u...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-03-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07469-4 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850029144426938368 |
|---|---|
| author | Cuiping Guo Wensheng Li Yi Liu Abdoul Razak Mahaman Yacoubou Jianzhi Wang Rong Liu Shusheng Li Xiaochuan Wang |
| author_facet | Cuiping Guo Wensheng Li Yi Liu Abdoul Razak Mahaman Yacoubou Jianzhi Wang Rong Liu Shusheng Li Xiaochuan Wang |
| author_sort | Cuiping Guo |
| collection | DOAJ |
| description | Abstract Sepsis-associated encephalopathy (SAE) is a severe neurological syndrome marked by widespread brain dysfunctions due to sepsis. Despite increasing data supporting the hypothesis of neuronal damage, the exact mechanism of sepsis-related cognitive disorders and therapeutic strategies remain unclear and need further investigation. In this study, a sepsis model was established in C57 mice using lipopolysaccharide (LPS). The findings demonstrated that LPS exposure induced neuronal loss, synaptic and cognitive deficits accompanied by mitochondrial damage. Bioinformatics and western blot analyses demonstrated a significant increase in Lipocalin-2 (LCN2) during sepsis as a key hub gene involved in immune and neurological inflammation. Interestingly, the recombinant LCN2 protein exhibited similar effects on synaptic dysfunction and cognitive deficits in C57 mice. Conversely, downregulating LCN2 effectively nullified the impact of LPS, leading to the amelioration of synaptic and cognitive deficits, neuronal loss, and reactive oxygen species (ROS)-associated mitochondrial damage. These findings suggest a novel etiopathogenic mechanism of SAE, which is initiated by the increased LCN2, leading to neuronal loss and cognitive deficit. Inhibition of LCN2 could be therapeutically beneficial in treating sepsis-induced synaptic and cognitive impairments. |
| format | Article |
| id | doaj-art-69cc9f3adf1d4f66bc24f469fa1f0de0 |
| institution | DOAJ |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-69cc9f3adf1d4f66bc24f469fa1f0de02025-08-20T02:59:37ZengNature Publishing GroupCell Death and Disease2041-48892025-03-0116111710.1038/s41419-025-07469-4LCN2 induces neuronal loss and facilitates sepsis-associated cognitive impairmentsCuiping Guo0Wensheng Li1Yi Liu2Abdoul Razak Mahaman Yacoubou3Jianzhi Wang4Rong Liu5Shusheng Li6Xiaochuan Wang7Department of Emergency Medicine & Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and TechnologyInstitute of Biomedical Sciences, School of Medicine, Hubei Key Laboratory of Cognitive and Affective Disorders, Jianghan UniversityDepartment of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Emergency Medicine & Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Emergency Medicine & Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyAbstract Sepsis-associated encephalopathy (SAE) is a severe neurological syndrome marked by widespread brain dysfunctions due to sepsis. Despite increasing data supporting the hypothesis of neuronal damage, the exact mechanism of sepsis-related cognitive disorders and therapeutic strategies remain unclear and need further investigation. In this study, a sepsis model was established in C57 mice using lipopolysaccharide (LPS). The findings demonstrated that LPS exposure induced neuronal loss, synaptic and cognitive deficits accompanied by mitochondrial damage. Bioinformatics and western blot analyses demonstrated a significant increase in Lipocalin-2 (LCN2) during sepsis as a key hub gene involved in immune and neurological inflammation. Interestingly, the recombinant LCN2 protein exhibited similar effects on synaptic dysfunction and cognitive deficits in C57 mice. Conversely, downregulating LCN2 effectively nullified the impact of LPS, leading to the amelioration of synaptic and cognitive deficits, neuronal loss, and reactive oxygen species (ROS)-associated mitochondrial damage. These findings suggest a novel etiopathogenic mechanism of SAE, which is initiated by the increased LCN2, leading to neuronal loss and cognitive deficit. Inhibition of LCN2 could be therapeutically beneficial in treating sepsis-induced synaptic and cognitive impairments.https://doi.org/10.1038/s41419-025-07469-4 |
| spellingShingle | Cuiping Guo Wensheng Li Yi Liu Abdoul Razak Mahaman Yacoubou Jianzhi Wang Rong Liu Shusheng Li Xiaochuan Wang LCN2 induces neuronal loss and facilitates sepsis-associated cognitive impairments Cell Death and Disease |
| title | LCN2 induces neuronal loss and facilitates sepsis-associated cognitive impairments |
| title_full | LCN2 induces neuronal loss and facilitates sepsis-associated cognitive impairments |
| title_fullStr | LCN2 induces neuronal loss and facilitates sepsis-associated cognitive impairments |
| title_full_unstemmed | LCN2 induces neuronal loss and facilitates sepsis-associated cognitive impairments |
| title_short | LCN2 induces neuronal loss and facilitates sepsis-associated cognitive impairments |
| title_sort | lcn2 induces neuronal loss and facilitates sepsis associated cognitive impairments |
| url | https://doi.org/10.1038/s41419-025-07469-4 |
| work_keys_str_mv | AT cuipingguo lcn2inducesneuronallossandfacilitatessepsisassociatedcognitiveimpairments AT wenshengli lcn2inducesneuronallossandfacilitatessepsisassociatedcognitiveimpairments AT yiliu lcn2inducesneuronallossandfacilitatessepsisassociatedcognitiveimpairments AT abdoulrazakmahamanyacoubou lcn2inducesneuronallossandfacilitatessepsisassociatedcognitiveimpairments AT jianzhiwang lcn2inducesneuronallossandfacilitatessepsisassociatedcognitiveimpairments AT rongliu lcn2inducesneuronallossandfacilitatessepsisassociatedcognitiveimpairments AT shushengli lcn2inducesneuronallossandfacilitatessepsisassociatedcognitiveimpairments AT xiaochuanwang lcn2inducesneuronallossandfacilitatessepsisassociatedcognitiveimpairments |