Autophagy dysfunction contributes to NLRP1 inflammasome-linked depressive-like behaviors in mice

• Published in: Journal of neuroinflammation 2024-01, Vol.21 (1), p.6-6, Article 6
• Main Authors: Zhu, Ya-Jing, Huang, Jing, Chen, Ru, Zhang, Yu, He, Xin, Duan, Wen-Xin, Zou, Yuan-Lei, Sun, Meng-Mei, Sun, Hui-Li, Cheng, Si-Min, Wang, Hao-Chuan, Zhang, Hao, Wu, Wen-Ning
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Animal models; Animals; Antidepressive Agents - pharmacology; Apoptosis; Aspartate; Autophagy; Autophagy (Cytology); BAX protein; Bcl-2 protein; Bcl-x protein; Behavior; Brain-derived neurotrophic factor; Caspase-3; CSDS; Cytokines; Cytokines - metabolism; Depression - metabolism; Depression, Mental; Depressive Disorder, Major - drug therapy; Development and progression; Ethanol; Gene expression; Health aspects; Hippocampus; Hippocampus - metabolism; Immunofluorescence; Immunoprecipitation; Inflammasomes - metabolism; Inflammation; Lymphocytes B; Lymphomas; Major depressive disorder; MDD; Medical research; Mental depression; Mice; mTOR; Neurological disorders; Neuroprotection; NLRP1 inflammasome; Oligomerization; Oligomers; Open-field behavior; Phagosomes; Phosphatidylinositol 3-Kinases - metabolism; PI3K/AKT; Protein-tyrosine kinase receptors; Proteinase 3; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Pyrin protein; Risk factors; RNA; Sirolimus - pharmacology; Social aspects; Social behavior; Social interactions; Sucrose; TOR Serine-Threonine Kinases - metabolism; Transmission electron microscopy; Tumor necrosis factor-TNF; Tyrosine; Western blotting
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-023-02995-4

Major depressive disorder (MDD) is a common but severe psychiatric illness characterized by depressive mood and diminished interest. Both nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 1 (NLRP1) inflammasome and autophagy have been reported to implicate in the pathological processes of depression. However, the mechanistic interplay between NLRP1 inflammasome, autophagy, and depression is still poorly known. Animal model of depression was established by chronic social defeat stress (CSDS). Depressive-like behaviors were determined by social interaction test (SIT), sucrose preference test (SPT), open field test (OFT), forced swim test (FST), and tail-suspension test (TST). The protein expression levels of NLRP1 inflammasome complexes, pro-inflammatory cytokines, phosphorylated-phosphatidylinositol 3-kinase (p-PI3K)/PI3K, phosphorylated-AKT (p-AKT)/AKT, phosphorylated-mechanistic target of rapamycin (p-mTOR)/mTOR, brain-derived neurotrophic factor (BDNF), phosphorylated-tyrosine kinase receptor B (p-TrkB)/TrkB, Bcl-2-associated X protein (Bax)/B-cell lymphoma-2 (Bcl2) and cleaved cysteinyl aspartate-specific proteinase-3 (caspase-3) were examined by western blotting. The mRNA expression levels of pro-inflammatory cytokines were tested by quantitative real-time PCR. The interaction between proteins was detected by immunofluorescence and coimmunoprecipitation. Neuronal injury was assessed by Nissl staining. The autophagosomes were visualized by transmission electron microscopy. Nlrp1a knockdown was performed using an adeno-associated virus (AAV) vector containing Nlrp1a-shRNA-eGFP infusion. CSDS exposure caused a bidirectional change in hippocampal autophagy function, which was activated in the initial period but impaired at the later stage. In addition, CSDS exposure increased the expression levels of hippocampal NLRP1 inflammasome complexes, pro-inflammatory cytokines, p-PI3K, p-AKT and p-mTOR in a time-dependent manner. Interestingly, NLRP1 is immunoprecipitated with mTOR but not PI3K/AKT and CSDS exposure facilitated the immunoprecipitation between them. Hippocampal Nlrp1a knockdown inhibited the activity of PI3K/AKT/mTOR signaling, rescued the impaired autophagy and ameliorated depressive-like behavior induced by CSDS. In addition, rapamycin, an autophagy inducer, abolished NLRP1 inflammasome-driven inflammatory reactions, alleviated depressive-like behavior and exerted a neuroprotective effect. Autophagy dysfunc