2. Academic Validation
  3. Inhibition of TREM-1 Ameliorates Lipopolysaccharide-induced Depressive-like Behaviors by Alleviating Neuroinflammation in the PFC via PI3K/Akt Signaling Pathway

Inhibition of TREM-1 Ameliorates Lipopolysaccharide-induced Depressive-like Behaviors by Alleviating Neuroinflammation in the PFC via PI3K/Akt Signaling Pathway

  • Behav Brain Res. 2023 May 2;114464. doi: 10.1016/j.bbr.2023.114464.
Anhui Fu 1,  Fei Qiao 1,  Hao Feng 1,  Qing Luo 2
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Nanchong Central Hospital, The Second Clinical Medical College of North Sichuan Medical College, Nanchong, China.
  • 2 Department of Ultrasound, Chonggang general hospital, Chongqing, China. Electronic address: [email protected].
PMID: 37142164 DOI: 10.1016/j.bbr.2023.114464
Abstract

Neuroinflammation is closely related to depression and is a key pathophysiological process of depression. Triggering receptor expressed on myeloid cells 1 (TREM-1) has been proven to exert proinflammatory effects in various diseases. However, the role of TREM-1 in depression has not been elucidated. Thus, we hypothesized that TREM-1 inhibition might have protective effects in depression. Here, lipopolysaccharide (LPS) was used to induce depressive-like behaviors in mice, LP17 was treated to inhibit TREM-1, and LY294002 was administrated to inhibit phosphatidylinositol 3-kinase (PI3K) which is one of the downstream of TREM-1. Physical and neurobehavioral tests, Western blot analysis, and immunofluorescence staining were performed in this study. We found that LPS caused significant depressive-like behaviors in mice, including body weight decline, anodynia (sucrose preference decrease), lack of locomotor activity, and desperation in tail suspension test (TST) and forced swimming test (FST). Next, we revealed that TREM-1 was expressed on microglia, neurons, and astrocytes in the prefrontal cortex (PFC) after LPS administration. TREM-1 inhibition by LP17 suppressed the expression of TREM-1 in the PFC. In addition, LP17 could alleviate neuroinflammation and microglial activation in the PFC. Meanwhile, LP17 could prevent damage of LPS to neuronal primary cilia and neuronal activity. Finally, we revealed that PI3K/Akt might exert crucial role in the protective effects of TREM-1 inhibition to depressive-like behaviors induced by LPS. Taken together, TREM-1 inhibition by LP17 could alleviate depressive-like behaviors induced by LPS by mitigating neuroinflammation in the PFC via PI3K/Akt signaling pathway. Finally, we demonstrated that TREM-1 might be a promising therapeutic target for treatment of depression.

Keywords

PI3K; depression; lipopolysaccharide; neuroinflammation; prefrontal cortex.

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