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Severe inflammation in C57/BL6 mice leads to prolonged cognitive impairment by initiating the IL-1β/TRPM2 pathway
Yujiao Yang1, Zhihua Yao2, Hushan Wang2
1Department of Anesthesiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China; Department of Anesthesiology, North Sichuan Medical College, Nanchong, Sichuan, China.
Background:
Sepsis could lead to chronic cognitive impairment by unclear molecular mechanisms. Transient receptor potential melastatin-2 (TRPM2) is essential against immunity-related activities and inflammation. Our study attempted to decipher the relationship between cognitive impairment caused by severe inflammation and TRPM2 expression levels.
Methods:
Severe inflammation was induced by intraperitoneally injecting C57/BL6 mice with a high dosage (5 mg kg-1) of Lipopolysaccharide (LPS). Fear conditioning and a Morris water maze test were performed to examine the cognitive abilities of the mice. Moreover, the signaling and expression of pro-inflammatory cytokines and TRPM2 were measured using Western blotting and Reverse transcription-polymerase chain reaction (RT-PCR). Flow cytometry and immunofluorescence staining helped to determine the astrocyte apoptosis rate.
Results:
Severe inflammation can lead to long-term cognitive impairment in C57/BL6 mice. The interleukin-1 beta (IL-1β) levels intra-hippocampus were significantly elevated until P14 post-LPS introduction. At both P7 and P14, there is an up-regulation of TRPM2 expression within hippocampus. Administration of recombinant IL-1β to astrocytes results in a significant up-regulation of TRPM2 expression. IL-1β or TRPM2 level knockdown helped counter the cognitive impairment caused by significant inflammation.
Conclusions:
A continuous increase in IL-1β levels within the hippocampus can lead to cognitive impairment by enhancing TRPM2 levels caused by severe inflammation.
Insights
Severe inflammation causes long-term cognitive impairment by increasing interleukin-1 beta (IL-1β) and TRPM2 levels in the hippocampus. Reducing these inflammatory markers can help mitigate cognitive deficits.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Sepsis can cause chronic cognitive impairment through unknown molecular pathways.
- Transient receptor potential melastatin-2 (TRPM2) plays a role in immune responses and inflammation.
- This study investigates the link between severe inflammation-induced cognitive deficits and TRPM2 expression.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying sepsis-induced cognitive impairment.
- To determine the role of TRPM2 in inflammation-related cognitive dysfunction.
- To explore the relationship between IL-1β and TRPM2 in the hippocampus.
Main Methods:
- Induced severe inflammation in C57/BL6 mice using lipopolysaccharide (LPS).
- Assessed cognitive function via fear conditioning and Morris water maze tests.
- Measured cytokine and TRPM2 expression using Western blotting and RT-PCR; analyzed astrocyte apoptosis via flow cytometry and immunofluorescence.
Main Results:
- Severe inflammation led to persistent cognitive impairment in mice.
- Hippocampal IL-1β levels remained elevated up to 14 days post-LPS.
- TRPM2 expression was upregulated in the hippocampus at 7 and 14 days post-LPS, and IL-1β administration increased TRPM2.
- Knockdown of IL-1β or TRPM2 ameliorated cognitive impairment.
Conclusions:
- Sustained hippocampal IL-1β elevation contributes to cognitive impairment by upregulating TRPM2.
- TRPM2 is a key mediator in inflammation-induced cognitive deficits.
- Targeting IL-1β and TRPM2 pathways may offer therapeutic strategies for sepsis-related cognitive dysfunction.
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