Targeting microglial autophagic degradation in NLRP3 inflammasome-mediated neurodegenerative diseases

Wu, Anguo; Zhou, Xiao-Gang; Qiao, Gan; Yu, Lu; Tang, Yong; Lu, Yan; Qiu, Wen-Qiao; Pan, Rong; Yu, Chong-Lin; Law, Betty Yuen‐Kwan; Qin, Da-Lian; Wu, Jianming

doi:10.1016/j.arr.2020.101202

Cited by 138 publications

(84 citation statements)

References 240 publications

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“…Activation of NLRP3 inflammasome involves in damage to the mitochondria and the increased production of reactive oxygen species (ROS) (32). Autophagy plays a role in the removal of misfolded proteins, and the clearance of damaged mitochondria and ROS (33). Notably, we demonstrated that alleviated autophagosome formation is closely related to the effect of spvC on NLRP3.…”

Section: Discussionmentioning

confidence: 79%

Salmonella spvC Gene Inhibits Autophagy of Host Cells and Suppresses NLRP3 as Well as NLRC4

Zhou

Gao

et al. 2021

Front. Immunol.

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Salmonella spvC gene, encoding a phosphothreonine lyase on host mitogen-activated protein kinases, facilitates systemic infection of Salmonella while the precise mechanisms remain elusive. Autophagy and pyroptosis dependent on the activation of inflammasomes, as parts of innate immune response, contribute to host defense against Salmonella infection. Recently, we reported that spvC could inhibit pyroptosis. To explore the effect of spvC on autophagy and the relationship between its function in pyroptosis and autophagy, infection models of macrophages J774A.1 and epithelial HeLa cells co-cultured with Salmonella Typhimurium wild type, spvC deletion, site-directed mutant which lacks phosphothreonine lyase activity, or complemented strain were established. The levels of LC3 turnover and Beclin 1 of J774A.1 cells were determined by western blot. Confocal laser scanning microscopy was used to visualize the autophagic flux after being transfected with mRFP-GFP-LC3 plasmid in HeLa cells. Results showed that SpvC inhibited autophagosome formation through its phosphothreonine lyase activity. Additionally, analysis of nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) and NLR with CARD domain-containing 4 (NLRC4) in J774A.1 cells indicated that spvC decreased the protein levels of NLRP3 and NLRC4, which were significantly changed by autophagy inhibitor Bafilomycin A1. Together, our observations reveal a novel mechanism of spvC in Salmonella pathogenesis and host inflammatory response via inhibiting autophagy and NLRP3 as well as NLRC4. These pathways and their subversion by diverse pathogen virulence determinants are expected to throw light on the design of anti-infective agents.

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Section: Discussionmentioning

confidence: 79%

Salmonella spvC Gene Inhibits Autophagy of Host Cells and Suppresses NLRP3 as Well as NLRC4

Zhou

Gao

et al. 2021

Front. Immunol.

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“…It has been shown that induction of autophagy in general is effective in the mitigation of this inflammatory condition [317]. Specifically, induction of autophagy in microglia ameliorates neuroinflammation due to degradation of misfolded proteins, damaged mitochondria (i.e., mitophagy), and activated inflammasomes [318].…”

Section: Role Of Impaired Autophagy In Neuroinflammationmentioning

confidence: 99%

“…Interestingly, it is shown that TREM2 [242] and APOE4 [353,354] (two genes associated with sporadic AD) negatively regulate autophagy in cells. Additionally, it has been reported that NLRP3 negatively affects autophagy flux through downregulation of PINK1 leading to accumulation of misfolded proteins in AD [318,320,355,356].…”

Section: Role Of Neuroinflammation In Impairment Of Autophagymentioning

confidence: 99%

Alzheimer’s Disease Pathogenesis: Role of Autophagy and Mitophagy Focusing in Microglia

Eshraghi

Adlimoghaddam

Mahmoodzadeh

et al. 2021

IJMS

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Alzheimer’s disease (AD) is a debilitating neurological disorder, and currently, there is no cure for it. Several pathologic alterations have been described in the brain of AD patients, but the ultimate causative mechanisms of AD are still elusive. The classic hallmarks of AD, including am-yloid plaques (Aβ) and tau tangles (tau), are the most studied features of AD. Unfortunately, all the efforts targeting these pathologies have failed to show the desired efficacy in AD patients so far. Neuroinflammation and impaired autophagy are two other main known pathologies in AD. It has been reported that these pathologies exist in AD brain long before the emergence of any clinical manifestation of AD. Microglia are the main inflammatory cells in the brain and are considered by many researchers as the next hope for finding a viable therapeutic target in AD. Interestingly, it appears that the autophagy and mitophagy are also changed in these cells in AD. Inside the cells, autophagy and inflammation interact in a bidirectional manner. In the current review, we briefly discussed an overview on autophagy and mitophagy in AD and then provided a comprehensive discussion on the role of these pathways in microglia and their involvement in AD pathogenesis.

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“…Overactivation of the inflammasome, however, is usually detrimental to cellular and body health. At present, it has also been found ( 36 ) that there are various mechanisms in cells of the body for the negative regulation of the activation of NLRP3 inflammasome, which may function through the mechanism of receptor binding and blocking, the mechanism of autophagy, or by interfering with the expression mechanism of related genes ( Figure 2 ). For example, mir-223 negatively regulates the activation of NLRP3 inflammasomes by inhibiting the expression of NLRP3 gene at the transcriptional level.…”

Section: Negative Regulation Of Nlrp3 Inflammasome Activationmentioning

confidence: 99%

Activation of NLRP3 Inflammasome and Onset of Alzheimer’s Disease

Bai

Zhang

2021

Front. Immunol.

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The nucleotide-binding domain leucine-rich repeat and pyrin domain containing receptor protein 3 (NLRP3) is an important pattern recognition receptor in human innate immunity. Activation of the NLRP3 inflammasome play a key role in the pathogenesis of Alzheimer’s disease (AD). Theories explaining activation of the NLRP3 inflammasome include the reactive oxygen species theory, the lysosomal damage theory and the mitochondrial DNA theory. The NLRP3 activation promotes occurrence of AD by producing IL-1β, IL-18 and other cytokines, and then by affecting the deposition of Aβ and tau proteins. Over-activated NLRP3 inflammasome often impair cell function and induces immune-related diseases. Some mechanisms have been found to negatively regulate activation of the NLRP3 inflammasome, which may be through receptor binding blocking mechanism, autophagy related mechanism, abnormal cytokine secretion mechanism, or interference related gene expression regulation mechanism. In this review, we summarize the possible mechanisms by which the activation of NLRP3 inflammasomes affects the pathogenesis of AD, and the recent advances in the prevention and treatment of AD by controlling the activation of NLRP3 inflammasomes. By researching the activation or inactivation of NLRP3 inflammasome, it is possible to reveal the pathogenesis of AD from a new perspective and provide a new idea for the prevention and treatment of AD.

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Targeting microglial autophagic degradation in NLRP3 inflammasome-mediated neurodegenerative diseases

Cited by 138 publications

References 240 publications

Salmonella spvC Gene Inhibits Autophagy of Host Cells and Suppresses NLRP3 as Well as NLRC4

Salmonella spvC Gene Inhibits Autophagy of Host Cells and Suppresses NLRP3 as Well as NLRC4

Alzheimer’s Disease Pathogenesis: Role of Autophagy and Mitophagy Focusing in Microglia

Activation of NLRP3 Inflammasome and Onset of Alzheimer’s Disease

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