ReviewTargeting microglial autophagic degradation in NLRP3 inflammasome-mediated neurodegenerative diseases
Introduction
Neurodegenerative diseases are progressive diseases characterized by the loss of neuronal structure or function associated with neuronal death (Ross and Poirier, 2004). Emerging evidence points to the inflammatory responses in the central nervous system (CNS) as a major cause and a common feature in neurodegenerative diseases (Amor et al., 2014, 2010; Stephenson et al., 2018). The innate immune system has been viewed as the key first line of defense that protects the body against invading pathogens resulting from tissue injury, dysregulation of the metabolism, and infection (Hato and Dagher, 2015).
Inflammasomes, an important component of the innate immune system, are a type of macromolecular protein complex that assemble in the cytosol after microglia or astrocytes sense the pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) by the germline-encoded pattern-recognition receptors (PRRs) (Guo et al., 2015; Lampron et al., 2013; Latz et al., 2013). Upon stimulation by PAMPs/DAMPs, such as misfolded proteins, known as a common feature of neurodegenerative diseases, the nucleotide-binding oligomerization domain (NOD) and leucine-rich repeat (LRR)-containing proteins (NLRs) or absent in melanoma 2 (AIM2)-like receptors (ALRs) are oligomerized to a caspase-1-activating scaffold.
The adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is composed of a pyrin domain (PYD) functioning as an adaptor that links the PYD of the inflammasome sensor, and a caspase recruitment domain (CARD) of pro-caspase-1. ASC associates with pro-caspase-1 via its CARD–CARD interactions and induces caspase-1 activation. Then, both pro-interleukin (IL)-1β and pro-IL-18 are cleaved into the mature forms IL-1β and IL-18 by the active caspase-1, which ultimately induces inflammatory responses and leads to neuronal death (Guo et al., 2015). NOD-, LRR-, and pyrin domain-containing 3 (NLRP3), the most fully characterized inflammasome, is widely expressed in the microglia and has been demonstrated to mediate inflammation in neurodegenerative diseases. Emerging evidence indicates that the NLRP3 inflammasome positively regulates the progression of neurodegenerative diseases, while the genetic knockout and the specific inhibitors of the NLRP3 inflammasome or its components were demonstrated to inhibit the NLRP3 inflammasome-mediated neuroinflammation (Heneka et al., 2013; Venegas et al., 2017). Therefore, there are many specific inhibitors targeting NLRP3, caspase-1, or the NLRP3 inflammasome that have been identified to inhibit the inflammatory responses in neurodegenerative diseases (Daniels et al., 2016; Flores et al., 2018; Gordon et al., 2018).
Autophagy, acting as a protective mechanism, maintains normal cellular function and homeostasis by degrading the engulfed substances, including misfolded proteins and damaged mitochondria, in autophagosomes with lysosomal action (Glick et al., 2010; Gordon et al., 2018; Mizushima and Komatsu, 2011). Emerging evidence indicates that the deficiency or inhibition of autophagy aggravates the NLRP3 inflammasome-mediated inflammation and the pathology of neurodegenerative diseases (Cho et al., 2014; Yuan et al., 2018a), while the autophagy inducers, such as rapamycin, metformin, and AICA Riboside (AICAR), effectively inhibit the over-activation of the NLRP3 inflammasome, and are beneficial in neurodegenerative diseases (Cheng et al., 2017; Cho et al., 2014). Therefore, the autophagy inducers targeting microglial autophagy not only clear the misfolded proteins and damaged mitochondria but also degrade the NLRP3 inflammasome or its components. Studies showed that the combined use of the specific inhibitors of the NLRP3 inflammasome with autophagy inducers targeting microglial autophagic degradation were more effective than a single treatment as revealed by both cellular and animal models of neurodegenerative diseases (Chen et al., 2019; Xu et al., 2019).
In this review, we depicted the mechanism of NLRP3 inflammasome activation and summarized the latest findings, including the NLRP3 inflammasome-mediated inflammation in neurodegenerative diseases, microglial autophagic degradation for misfolded protein aggregations, damaged mitochondria and its resultant reactive oxygen species (ROS), and in particular the NLRP3 inflammasome or its components. Finally, we concluded that the over-activated NLRP3 inflammasome-mediated inflammation was not only the consequence and pathologic feature but also a risk factor that aggravates the pathogenesis and progression of neurodegenerative diseases. The autophagy enhancers targeting microglial autophagy and their combined use with the specific inhibitors of the NLRP3 inflammasome or its components in the inhibition of NLRP3 inflammasome-mediated neuroinflammation requires further preclinical and clinical validations in the future.
Section snippets
The inflammasomes and the NLRP3 inflammasome
Inflammasomes were first discovered in 2002 (Martinon et al., 2002). Inflammasomes are cytosolic multiprotein platforms that trigger the secretion of pro-inflammatory cytokines, such as IL-1β and IL-18, upon stimulation by PAMPs/DAMPs to exert innate immune defenses. Inflammasomes are composed of proteins, including a sensor protein from the cytosolic NLR, ALR, or pyrin, an adaptor ASC and pro-caspase-1 (Guo et al., 2015; Lampron et al., 2013; Latz et al., 2013). The NLR family consists of CARD
The key role of microglia in NLRP3 inflammasome-mediated neuroinflammation
Neurodegenerative diseases are a group of neurologic disorders characterized by the progressive loss of neurons in the CNS. The main symptoms include memory loss, forgetfulness, agitation, and motor deficit. Although many studies demonstrated that the misfolded proteins gradually aggregate in neurons and induce neuronal toxicity and death, certain clues increasingly point to immune responses in the CNS as an important and common feature of various neurodegenerative diseases (Scheiblich et al.,
PAMPs/DAMPs induce NLRP3 inflammasome over-activation in neurodegenerative diseases
In neurodegenerative diseases, the NLRP3 inflammasome has been reported to be activated by various PAMPs/DAMPs, including misfolded protein aggregations, such as Aβ, Tau, α-synuclein, and mutant huntingtin (mHtt); neurotoxins, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6−OHDA), and rotenone; viruses; and drugs of abuse via the lysosomal membrane destabilization resulting in a K+ efflux and Ca2+ influx, as well as the generation of ox-mtDNA and mtROS from
Over-activated NLRP3 inflammasome-mediated neuroinflammation aggravates the pathology of neurodegenerative diseases
To date, emerging evidence indicates that there is a close correlation between the over-activated NLRP3 inflammasome in microglia and the pathology of neurodegenerative diseases (Gordon et al., 2018; Heneka et al., 2013; Ising et al., 2019; Tejera et al., 2019). As described above, the PAMPs/DAMPs, such as misfolded protein aggregations, neurotoxins, viruses, and drugs of abuse, over-activate microglia and the NLRP3 inflammasome in patients or animals with neurodegenerative diseases. Emerging
Microglial autophagy in NLRP3 inflammasome-mediated neuroinflammation
In inflammation-mediated neurodegenerative diseases, microglia, acting as the resident immune cells in CNS, protect the brain against injury by various types of pathogenic factors (Graeber et al., 2011; Voet et al., 2019a). The moderate activation of microglia exhibits a neuroprotective role that maintains brain homeostasis through releasing neurotrophic factors, engulfing the damaged neurons and PAMPs/DAMPs, as well as inducing repair of tissue. However, the excessive activation of microglia
Other specific inhibitors targeting the NLRP3 inflammasome or its components in neurodegenerative diseases
In addition to the autophagy inducers targeting microglial autophagic degradation of PAMPs/DAMPs such as misfolded proteins, damaged mitochondria, and the NLRP3 inflammasome, the specific inhibitors that inhibit the NLRP3 inflammasome or its components, including caspase-1, ASC, NLRP3, and GSDMD, were identified to significantly inhibit the over-activation of the NLRP3 inflammasome (Table 3). Caspase-1, also known as interleukin-1 converting enzyme (ICE), plays an important role in
Concluding remarks and future perspectives
The over-activated NLRP3 inflammasome has been characterized extensively and implicated in the development and progression of various neurodegenerative diseases. Misfolded protein aggregations, the common feature of neurodegenerative diseases, induce mitochondrial damage, ROS generation, lysosomal rupture, and cathepsins release. All the above risk factors result in the over-activation of the NLRP3 inflammasome in microglia. The over-activated NLRP3 inflammasome, in turn, aggravates the
Author contributions
Da-Lian Qin, Jian-Ming Wu, and An-Guo Wu conceived the paper, An-Guo Wu and Xiao-Gang Zhou wrote the original manuscript, Gan Qiao, Lu Yu, and Yong Tang collected the data in the table, Wen-Qiao Qiu, Rong Pan, Betty Yuen-Kwan Law, and Chong-Lin Yu revised the manuscript, An-Guo Wu and Lu Yan checked all the references and manuscript. All authors approved the final version of the manuscript.
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgments
This work was supported by Grants from the Joint project of Luzhou Municipal People’s Government and Southwest Medical University, China (grant no. 2020LZXNYDJ37, 2019LZXNYDJ02, 2018LZXNYD-YL05, 2018LZXNYD-ZK41, 2018LZXNYD-ZK42, and 2019LZXNYDJ05). The Grants from the National Natural Science Foundation of China (Grant No. 81903829, 81801398). The Science and Technology Planning Project of Sichuan Province, China (grant no. 2018JY0474, 2019JDPT0010, 2019YFSY0014, SYZ202076, SYZ202077, 2020086,
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These authors contributed equally to this work.