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J Neuroinflammation. 2018 Sep 4;15(1):252. doi: 10.1186/s12974-018-1296-0.

Hippocampal Mrp8/14 signaling plays a critical role in the manifestation of depressive-like behaviors in mice.

Author information

1
Department of Stress Medicine, Faculty of Psychology and Mental Health, Second Military Medical University, Shanghai, 200433, People's Republic of China.
2
Hainan Branch of Chinese PLA General Hospital, Sanya, 572013, People's Republic of China.
3
Department of Psychiatry, The 102nd Hospital of PLA, Changzhou, 213003, People's Republic of China.
4
Department of Psychiatry, Faculty of Psychology and Mental Health, Second Military Medical University, Shanghai, 200433, People's Republic of China.
5
Department of Navy Medicine, Second Military Medical University, Shanghai, 200433, People's Republic of China.
6
Department of Stress Medicine, Faculty of Psychology and Mental Health, Second Military Medical University, Shanghai, 200433, People's Republic of China. cljiang@vip.163.com.

Abstract

BACKGROUND:

Depression is one of the most common mental disorders characterized mainly by low mood and loss of interest or pleasure. About a third of patients with depression do not respond to classic antidepressant treatments. Recent evidence suggests that Mrp8/14 (myeloid-related protein 8/14) plays a crucial role in cognitive dysfunction and neuroinflammatory diseases, yet its role in mood regulation remains largely uninvestigated. In the present work, we explored the potential role of Mrp8/14 in the progression of depression.

METHODS:

After 4 weeks of chronic unpredictable mild stress (CUMS), depressive-like symptoms and Mrp8/14 were determined. To verify the effects of Mrp8/14 on depressive-like behaviors, the inhibitor TAK-242 and recombinant Mrp8/14 were used. Furthermore, the molecular mechanisms in Mrp8/14-induced behavioral and biological changes were examined in vivo and ex vivo.

RESULTS:

Four-week CUMS contributed to the development of depressive symptoms. Mrp8 and Mrp14 were upregulated in the hippocampus and serum after exposure to CUMS. Pharmacological inhibition of Mrp14 attenuated CUMS-induced TLR4/NF-κB signaling activation and depressive-like behaviors. Furthermore, central administration of recombinant Mrp8, Mrp14, and Mrp8/14 resulted in neuroinflammation and depressive-like behaviors. Mrp8/14-provoked proinflammatory effects and depressive-like behaviors were improved by pretreatment with a TLR4 inhibitor. Moreover, pharmacological inhibition of TLR4 reduced the release of nitric oxide and reactive oxygen species in Mrp8/14-activated BV2 microglia.

CONCLUSIONS:

These data suggest that the hippocampal Mrp8/14-TLR4-mediated neuroinflammation contributes to the development of depressive-like behaviors. Targeting the Mrp8/14 may be a novel promising antidepressant approach.

KEYWORDS:

Depression; Hippocampus; Myeloid-related protein 8/14; Neuroinflammation; Stress; TLR4

PMID:
30180864
PMCID:
PMC6122683
DOI:
10.1186/s12974-018-1296-0
[Indexed for MEDLINE]
Free PMC Article

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