Involvement of the microglial NLRP3 inflammasome in the anti-inflammatory effect of the antidepressant clomipramine

Wenqing Gong; Shanshan Zhang; Ying Zong; Michael Halim; Zhonggan Ren; Yalin Wang; Yuanyuan Ma; Bing Li; Lixiang Ma; Guomin Zhou; Jin Yu; Junhai Zhang; Qiong Liu

doi:10.1016/j.jad.2019.05.009

Involvement of the microglial NLRP3 inflammasome in the anti-inflammatory effect of the antidepressant clomipramine

J Affect Disord. 2019 Jul 1:254:15-25. doi: 10.1016/j.jad.2019.05.009. Epub 2019 May 5.

Authors

Wenqing Gong¹, Shanshan Zhang², Ying Zong³, Michael Halim⁴, Zhonggan Ren⁵, Yalin Wang⁶, Yuanyuan Ma⁷, Bing Li⁸, Lixiang Ma⁹, Guomin Zhou¹⁰, Jin Yu¹¹, Junhai Zhang¹², Qiong Liu¹³

Affiliations

¹ Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, China. Electronic address: 14211010033@fudan.edu.cn.
² Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, China. Electronic address: 16211010040@fudan.edu.cn.
³ Department of Health Toxilogy, Colleage of Tropical Medicine and Public Health, Second Military Medical University, Shanghai, China. Electronic address: zongying@cti-cert.com.
⁴ Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, China. Electronic address: 13301056020@fudan.edu.cn.
⁵ Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, China. Electronic address: 16211010037@fudan.edu.cn.
⁶ Department of Integrative Medicine and Neurobiology School of Basic Medical Sciences, Shanghai, China. Electronic address: wangyalin@fudan.edu.cn.
⁷ Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University. Shanghai, China. Electronic address: mayuanyuan@fudan.edu.cn.
⁸ Jinshan Hospital of Fudan University, Shanghai, China. Electronic address: libing22@126.com.
⁹ Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, China. Electronic address: lxma@fudan.edu.cn.
¹⁰ Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, China; Key Laboratory of Medical Imaging Computing and Computer Assisted Intervention of Shanghai, Shanghai, China. Electronic address: gmzhou@shmu.edu.cn.
¹¹ Department of Integrative Medicine and Neurobiology School of Basic Medical Sciences, Shanghai, China. Electronic address: yujin@shmu.edu.cn.
¹² Department of Radiology, Huashan Hospital, Fudan University, 12 Wulumuqi Rd. middle, Shanghai 200040, China. Electronic address: jhzhang007@fudan.edu.cn.
¹³ Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, China; Key Laboratory of Medical Imaging Computing and Computer Assisted Intervention of Shanghai, Shanghai, China. Electronic address: liuqiong@fudan.edu.cn.

PMID: 31082627
DOI: 10.1016/j.jad.2019.05.009

Abstract

Background: Depression has recently been referred to as a neuroimmune disease because it is characterized by inflammatory changes in the cerebral cortex and hippocampus. Studies have demonstrated that microglial activation plays a crucial role in releasing inflammatory cytokines in the central nervous system (CNS), thereby contributing to depression, the mechanism underlying which remains unclear.

Methods: First, we examined microglial activation and inflammatory changes in C57BL/6 male mice injected with lipopolysaccharide (LPS; 1 mg/kg), which leads to depressive behaviors in mice that were attenuated by the antidepressant clomipramine. Second, we utilized a BV2 cell line and primary microglial cultures to determine the inflammatory response in vitro, and the effects of clomipramine exerted on the inflammatory response using real-time polymerase chain reaction and ELISA. Third, we utilized NLRP3 (NOD-like receptor protein 3) knock-out (KO) mice to prove that NLRP3 is involved in the effects of clomipramine.

Results: The results showed that LPS injection induced depressive-like behaviors in mice, as assessed using several behavioral tests including body weight, and forced swimming and tail suspension tests. The LPS-induced expression of interleukin-1beta (IL-1β), IL-6, and tumor necrosis factor alpha could be downregulated by clomipramine pre-treatment both in vivo and in vitro. The inhibitory effect of clomipramine on the LPS-induced increase in cytokines was found at both the protein and gene levels. Clomipramine significantly reduced the LPS-induced increase in NLRP3 gene expression in BV2 cells. Furthermore, we utilized NLRP3 KO mice to explore whether NLPP3 was involved in this process and found that clomipramine treatment inhibits the LPS-induced increased expression of IL-1β.

Conclusion: These results imply that clomipramine could attenuate depressive behaviors and neuroinflammation induced by LPS via partial regulation of NLRP3.

Keywords: Clomipramine; Depression; IL-1β; LPS; Microglia; NLRP3.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Inflammatory Agents / pharmacology*
Antidepressive Agents / pharmacology*
Clomipramine / pharmacology*
Cytokines / metabolism
Depression / chemically induced
Depression / drug therapy
Depressive Disorder / metabolism
Hippocampus / drug effects
Hippocampus / metabolism
Inflammasomes / drug effects
Inflammasomes / metabolism
Lipopolysaccharides / pharmacology
Male
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Knockout
Microglia / metabolism*
NLR Family, Pyrin Domain-Containing 3 Protein / deficiency
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*

Substances

Anti-Inflammatory Agents
Antidepressive Agents
Cytokines
Inflammasomes
Lipopolysaccharides
NLR Family, Pyrin Domain-Containing 3 Protein
NLRP3 protein, human
Nlrp3 protein, mouse
Clomipramine