International Immunopharmacology 49 (2017) 155–160

Contents lists available at ScienceDirect

International Immunopharmacology
journal homepage: www.elsevier.com/locate/intimp

Review

Amyloidogenic proteins associated with neurodegenerative diseases activate MARK

the NLRP3 inflammasome
Qian-hang Shaoa, Xiao-ling Zhanga, Peng-fei Yanga, Yu-he Yuana,⁎, Nai-hong Chena,b,⁎
a
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical
Sciences and Peking Union Medical College, Beijing 100050, China
b
College of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China

A R T I C L E I N F O A B S T R A C T

Keywords: Neuroinflammation has been shown as an essential factor in the pathogenesis of neurodegenerative diseases,
α-Synuclein such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, and Multiple Sclerosis.
Amyloid-β Furthermore, activated microglia and increased pro-inflammatory cytokines are the major hallmarks in neuro-
Inflammation degenerative diseases. A multimolecular complex named as inflammasome is involved in the process of in-
NLRP3 inflammasome
flammatory response, which can activate inflammatory caspases, leading to the cleavage and secretion of in-
Neurodegenerative disease
flammatory cytokines, and finally generates a potent inflammatory response. In neurodegenerative diseases, it
has been widely assumed that some types of amyloid proteins might be the triggers to activate the NLRP3
inflammasome. In this review, we summarize the current researches about the role of NLRP3 inflammasome, by
reviewing the main studies in vitro and in vivo experiments and discuss the potential for new therapeutic in-
terventions in neurodegenerative diseases.

1. Introduction disorders [6,7]. Interleukin-1β (IL-1β) has been demonstrated to be a

primary mediator leading to neurodegenerative diseases, and its
Neurodegenerative diseases in the central nervous system (CNS) abatement could account for the neuroprotective function in vitro and
with inferior regenerative capacity are fundamentally characterized by in vivo experiments [8]. During the process of inflammatory response,
its distinct pathologic mechanisms, including axonal structure and its production is regulated by a kind of multiprotein complexes termed
transport disruption, released harmful factors to extracellular matrix, as inflammasome. The assembled inflammasome contributes to the
and neuroinflammation. Therefore, the therapies of neurodegenerative cleavage of procaspase-1 to mature caspase-1, and then mature caspase-
diseases are faced with many challenges [1]. Neuroinflammation is an 1 orderly activates the IL-1 pro-inflammatory cytokine [9,10]. In-
important innate immune system response to injury and numerous flammasome is considered as an intracellular sensor for infectious pa-
stimuli such as pathogens and metabolic toxic wastes [2]. Thus, neu- thogens as well as for host danger signals associated with neurode-
roinflammation is now regarded as a crucial response not only to acute generative diseases [11]. It has been widely suggested that some similar
injury in the CNS, but also to neurodegenerative diseases [3]. Although aggregated deposits, which are formed by amyloid fibrils of specific
unstable inflammation may not represent a central factor, many data in proteins, such as amyloid-β protein in Alzheimer's disease (AD), α-sy-
animal models indicate that triggered inflammatory responses are in- nuclein protein in Parkinson's Disease (PD) and amyloid protein in
volved in the pathological progression of neurodegenerative disease Huntington's disease (HD), play important roles in the pathogenesis of
[4]. Microglia cells are the major phagocytes in the CNS and quickly related diseases [12,13]. These proteins share in a common trend to
respond to pathogenic stimuli to protect the microenvironment of the form amyloid-like structures and alter towards folding pathways, along
brain [5]. Additionally, abnormal activation of microglia and the in- with their intrinsic structure, which called cross-β structure. This spe-
cremental secretion of many pro-inflammatory cytokines have been cific structure may represent a new generic amyloid fibrils recognized
generally observed during the development of neurodegenerative by the innate immune system [14]. In addition, accumulating evidences

Abbreviations: AD, Alzheimer's disease; ANSC, adult neural stem cell; Aβ, amyloid-β protein; CNS, central nervous system; DAMPs, danger-associated molecular patterns; IL-1, in-
terleukin-1; LBs, Lewy bodies; NFTs, neurofibrillary tangles; NLRs, NOD-like receptors; PAMPs, pathogen-associated molecular patterns; PD, Parkinson's disease; PRRs, pattern re-
cognition receptors; ROS, reactive oxygen species; SNpc, substantia nigra pars compacta; TLRs, toll-like receptors
⁎
Corresponding authors at: Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, I, Xiannongtan Street,
Xicheng District, Beijing 100050, China.
E-mail addresses: yuanyuhe@imm.ac.cn (Y.-h. Yuan), chennh@imm.ac.cn (N.-h. Chen).

http://dx.doi.org/10.1016/j.intimp.2017.05.027
Received 7 March 2017; Received in revised form 12 May 2017; Accepted 22 May 2017
1567-5769/ © 2017 Elsevier B.V. All rights reserved.
Q.-h. Shao et al. International Immunopharmacology 49 (2017) 155–160

suggest that unique amyloid proteins can be sensed by the NLRP3 in- fibrils [37]. Moreover, recent studies have illustrated cation flux, mi-
flammasome and provide an underlying mechanism for IL-1 production tochondrial dysfunction and ER stress are also involved in the activa-
in neurodegenerative diseases [15,16]. In this review, we discuss the tion of the NLRP3 inflammasome [38]. The truth that many stimuli
recent findings about NLRP3 inflammasome, speculate its potential role cause NLRP3 activation indicates that the NLRP3 inflammasome acts as
in neurodegenerative diseases, and present the challenges in targeting a major sensor of cellular damage signals. Depending on abundant ex-
NLRP3 inflammasome for therapeutic purposes. periments, the NLRP3 inflammasome activation has been considered
through three major ways: abnormal expression level of specific cations
[39,40], serious oxidative stress with reactive oxygen species (ROS)
2. The NLRP3 inflammasome and inflammatory cytokine IL-1 in production [41], and phagosomal dysfunction with the lysosome rup-
neurodegenerative diseases ture [42]. Tissue expression researches show that the expression of
NLRP3 inflammasome main components is found in the CNS [43].
The response of the innate immune system plays a significant role Recently, one study has definitively demonstrated that microglia can
against acute injury in the CNS by pattern recognition receptors (PRRs) express the main components of NLRP3 inflammasome but astrocyte
such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs). PRRs cannot [44]. Interestingly, microglial cells are the major response cells
mainly express at microglia, astrocyte and macrophage, which can act of immune system in the CNS. And specific relevant proteins of neu-
as intracellular sensors to recognize a variety of danger-associated rological diseases that are thought to be the triggers for NLRP3 in-
molecular patterns (DAMPs) and pathogen-associated molecular pat- flammasome activation in CNS cells, including amyloid-β [45] and α-
terns (PAMPs) [17,18]. There are more than twenty NLR genes in hu- synuclein [46]. Therefore, the NLRP3 signaling plays a critical role in
mans and over thirty NLR genes in mice [19,20]. NLRs are divided into the inflammatory response of the CNS.
different groups and each of them has unique response to DAMPs [21]. IL-1 is a master cytokine that mediates both the innate and adaptive
Every NLR family member differs from each other since they have immune responses, leading to the production of other cytokines such as
various N-terminal protein domain structures [22]. Among all kinds of IL-6 or tumor necrosis factor α (TNF-α) [6,47]. IL-1 is a 17 kDa protein
NLRs, the inflammasome-forming NLR is the most particularly studied classified into two distinct isoforms, IL-1α and IL-1β [48], and is the
complex. The concept of inflammasome was firstly described by Mar- initial identified cytokine related with active actions in the brain.
tinon et al. in the early 2000s, when many scientists reported the spe- Meanwhile, many studies have supported that pro-inflammatory IL-1β
cific identification of a caspase-triggering complex [23]. The in- plays a master role in the neurodegenerative diseases [11,49]. Re-
flammasome is an intracellular multiprotein complex, which is defined markably, activation of microglia by lipopolysaccharide (LPS) causes
by its exclusive NLR protein, including NLRP1 [24], NLRP3 [25], symptoms of PD in wild-type mice. However, it was observed that LPS-
NLRC4 [26], NLRP6 [27], NLRP7 [28], as well as the HIN-200 family induced functional changes of learning and memory did not occur in IL-
member named as AIM2, without NLR inflammasome receptor and 1-knockout (KO) mice [50]. In one research, IL-1 receptor antagonist
directly binding cytosolic DNA [29]. However, only several kinds of knockout mice showed up-regulation of microglial neuroinflammation
inflammasomes have been recognized in the CNS: the NLRP1 in- and enhanced neuronal damage caused by infusing human amyloid-β
flammasome in neuron, the NLRP2 inflammasome in astrocyte, and the when compared with wild-type mice [51]. Two signal pathways are
NLRP3 inflammasome in microglia. All inflammasomes generally have necessary in the production of biologically active IL-1β, the first signal
three main components, containing a nucleating PRR, apoptosis-asso- is needed to upregulate the level of mRNA, which can be achieved by
ciated speck-like adapter protein containing a CARD (ASC) and the the activation of NF-κB pathway via TLRs. Following this, the second
downstream effector enzyme caspase-1 [30] (Fig. 1). signal pathway is to assemble the inflammasome complex and cleavage
NLRP3 inflammasome is the most thoroughly discussed inflamma- of pro-IL-1β by caspase-1 activation [15,22,52]. Furthermore, the in-
some in the CNS so far, due to that a large number of signals can make it flammasome is proved to be a key regulator in the secretion process of
active [31], such as PAMPs, protozoan pathogens and toxins from IL-1β [53,54]. A variety of stimuli associated with infection or cellular
bacteria [32], viral components [33], fungal [34], in addition, DAMPs stress can cause the inflammasome assembly, and subsequently re-
such as extracellular ATP [35], various crystals [36], and amyloid-β sulting in the cleavage of caspase-1 from its pro-form to its en-
zymatically active form. The active caspase-1 constitutively mediated
the cleavage of several cytokines, such as pro-IL-1β and pro-IL-18 into
the mature forms IL-1β and IL-18 [55]. Additionally, all these cytokines
contribute to the pathological process of neurodegenerative diseases
[56,57].

3. The NLRP3 inflammasome and amyloid-β in AD

Alzheimer's disease (AD) is the most common neurodegenerative

disease, it is estimated that more than 27 million people are affected all
over the world [58]. In the AD patients' brains, there are two important
neuropathology markers, one is neurofibrillary tangles (NFTs) and the
other is senile (amyloid) plaques [59]. The senile plaques are located at
extracellular sections and surrounded by activated microglia and as-
trocyte, which are formed by the insoluble amyloid-β protein fibrils
(Aβ). What is more, Aβ is a pathological protein that has been found to
be most clearly associated with the pathogenesis [60]. Inflammation
significantly contributes to the pathogenic process of AD, with in-
creased expression of inflammatory cytokines and neurotoxins [61],
Fig. 1. The structure and function of NLRP3 inflammasome. The danger signals can cause
one important cytokine involved in AD is IL-1β [62]. Extensive evi-
assembly and activation of NLRP3 inflammasome. NLRP3 inflammasome results in cas-
pase-1 activation and subsequently activated caspase-1 leads to the maturation of IL-1β.
dences have demonstrated that Aβ fibrils have the unique structural
LRR, leucine-rich repeat; NACHT, nucleotide binding and oligomerization domain; PYD, features, which can be the pro-inflammatory signal identified by TLRs,
pyrin-only domain; ASC, apoptosis-related speck-like protein containing a caspase re- along with activating NF-κB pathway [45], phosphorylated cAMP re-
cruitment domain; CARD, caspase activation and recruitment domain. sponse element binding protein (CREB) [63] and finally inducing the

156
Q.-h. Shao et al. International Immunopharmacology 49 (2017) 155–160

activation of microglia [64,65]. Although the exact pathogenesis of AD although it is already clear that α-synuclein protein is related in this
is not fully understood, it is considered that Aβ accumulation induces process.
persistent inflammation leading to neuronal dysfunction, which is Numerous studies have reported that aggregated α-synuclein is
suggested to be a potential mechanism of the progressive neurode- toxic to microglia, furthermore, α-synuclein abnormal regulation exerts
generation in AD [66]. a critical role in PD pathology [85,86]. In addition to amyloid-β, we
Recently, the activation of the NLRP3 inflammasome attracts much focused on the possibility of aggregated α-synuclein on NLRP3 in-
attention, which may be an alternative signaling pathway of Aβ binding flammasome activation, and its pro-inflammatory abilities as an amy-
downstream [67,68]. Further supports for this idea come from studies loidogenic peptide [46,87]. Current experimental results have demon-
of a vivo experiment, double transgenic mice associated with familial strated that aggregated α-synuclein acts as an endogenous disease-
AD mutations which have human APP protein over expression, when related signal, and induces microglia to release pro-inflammatory cy-
the NLRP3 inflammasome have an apparent deficiency, it performs an tokines such as TNF-α and IL-1β [87,88]. It is potent that aggregated
improvement in AD pathology and is protected from the tissue damage and misfolded protein is sensed by the NLRP3 inflammasome, providing
[68,69]. In vitro, primary microglia stimulated by fibrillar Aβ increases a unique mechanism for IL-1β production [15]. Specially, two hall-
the release of IL-1βand the process depends on the activation of cas- marks of inflammasome activation, mature IL-1β release and caspase-1
pase-1 and NLRP3 inflammasome [70]. Importantly, in this experiment, activation are found to be enhanced in the substantia nigra of PD pa-
it has also indicated that Aβ toxicity owing to IL-1β can be removed by tients [89]. In addition, some work data provide the evidences that the
the genetic deletion of caspase-1 [37]. In the vivo and vitro experiments, pro-inflammatory activity is exerted by fibrillar and monomeric α-sy-
these data showed that Aβ fibrils could provide both priming and ac- nuclein, finding that both of them can induce monocytes to promote the
tivation signals. Activation of the TLR pathway represented “signal 1” expression of pro-IL-1β, engaging with cell-membrane receptor TLR.
and Aβ fibrils stimulated a dramatic upregulation of IL-1β and TNF-α But only α-synuclein fibrils can induce the release of the mature form of
mRNA and an increase in pro-IL-1β. Aβ fibrils also clearly provided IL-1β, thereby activating NF-κB pathway and the NLRP3 inflamma-
“signal 2” which involved activation of the NLRP3inflammasome and some, respectively [46,90,91]. In many researches, it supports the
conversion of pro-IL-1β to mature IL-1β [71,72]. Hence, it is clear that opinion that α-synuclein oligomer is the primary neurotoxic form in the
Aβ fibrils are able to stimulate both priming and activation of the process of disease [92], whereas surprisingly, oligomer is unable to
NLRP3 inflammasome, and the activated NLRP3 inflammasome in mi- trigger NLRP3 inflammasome assembly and induce IL-1β secretion
croglia is fundamental for IL-1β maturation and secretion [68,73]. As [90]. α-Synuclein fibrils have their intrinsic cross-β structure, which
shown in recent researches, some findings prove that the NLRP3 in- could be identified by innate immunity and activate the inflammasome.
flammasome was activated when it sensed the lysosomal rupture, In one research, experimental results show that α-synuclein fibrils can
whereby the phagocytosed Aβ triggered an abnormal lysosomal re- induce damage of proliferation in neurospheres in adult neural stem
sponse and release of lysosomal protease cathepsin B [74]. Cathepsin B cells (ANSCs) and activate both TLR/NF-κB pathway and NLRP3/cas-
is associated with the pathogenesis of AD, plenty of cathepsin B is found pase-1 signals in ANSCs. Both NLRP3 inflammasome knockdown and
in activated microglia surrounding the senile plaques [75]. Inhibition of caspase-1 knockout could recover impaired neurogenesis in ANSCs.
the cathepsin B can apparently suppress NLRP3 inflammasome activa- These findings completely prove that NLRP3-inflammasome-mediated
tion, decrease Aβ deposition in the brain and improve spatial memory inflammatory pathway plays an essential role in the process of neuro-
[76]. In one recent context, using Aβ treated rat primary microglial genesis impairment induced by α-synuclein [91,93].
cells, experimental data suggest cathepsin B plays an essential role in Meanwhile, experimental studies have demonstrated that ag-
the process of NLRP3 inflammasome activation [77]. However, the in- gregated α-synuclein can be internalized by the cellular endocytic
depth mechanisms of cathepsin B and whether this phenomenon can pathways [94] and the internalized α-synuclein generates a rupture of
exist in AD animal models remain unclear. Additionally, autophagy is intracellular lysosomes. This rupture induces a cathepsin B dependent
similarly essential for the regulation of Aβ-induced NLRP3 inflamma- increase of ROS production in THP-1 cell [95], finally results in NLRP3
some activation. Study demonstrates that autophagic process in mi- inflammasome activation in these cells [96]. The observation that α-
croglia is impaired during Aβ treatment, resulting in counteracting Aβ synuclein fibrils induced-inflammasome activation in similar cell line of
clearance and serious deposition, it may aggravate inflammatory re- microglia convinces us that the NLRP3 inflammasome is relevant to the
sponse and activation of NLRP3 inflammasome [78] (Fig. 2). In con- neuroinflammatory in PD. Moreover, experiment investigates the role
clusion, studies above have offered a fine prospect to the therapeutic of phagocytosis and lysosomal function in α-synuclein peptides-induced
target of NLRP3 inflammasome in AD progression and further re- NLRP3 inflammasome activation, and interestingly finds that the in-
searches are needed to elucidate the detailed mechanisms of in- hibition of phagocytosis and lysosomal acidification significantly re-
flammasome contributing to AD pathology. strain inflammasome activation [97]. So all these results make a better
understanding of the mechanisms of the NLRP3 inflammasome activa-
4. The NLRP3 inflammasome and α-synuclein in PD tion, and find the direct interaction between microglia activation and
neurotoxic amyloidogenic peptides. In future, it is worthy to explore the
Parkinson's disease (PD) is the second most common age-related possibility of using an inflammasome antagonist as a new therapeutic
neurodegenerative disease in the world after Alzheimer's disease, and candidate in PD.
has influenced nearly 1.5% of the population over the age of 65 years
old [79,80]. PD is a multi-factorial disease, characterized by the pro- 5. Conclusion
gressive degeneration of dopamine (DA) neurons in the substantia nigra
pars compacta (SNpc) [80] and the presence of Lewy bodies (LBs) in the This review evaluates the role of inflammasome, especially em-
brain, mainly composed of aggregated and misfolded α-synuclein pro- phasizing the role of NLRP3 inflammasome in neurodegenerative dis-
tein, a neurodegenerative disease-related amyloidogenic peptides pro- eases. Neurodegenerative diseases are characterized by the aggregation
tein. Significant inflammatory markers such as activated microglia and of amyloidogenic protein, which are not considered to be typical in-
cytokines can be found in the SN of PD patients' brains and also have flammatory diseases, but sufficient evidences show that inflammatory
been found in several simulative animal models [81–83]. Thus neu- responses contribute to the pathogenesis. If we can control the neu-
roinflammation and immune system response can be considered not roinflammation, it may alleviate the process of neurodegeneration.
only as determinant risk factor in the disease progression but also as a NLRP3 inflammasome plays a vital role in the pathological process of
pathogenic factor in the occurring of PD [84]. The specific molecular neurodegenerative disorders, such as AD and PD, and acts as a common
mechanisms underlying neuroinflammation are still unknown, sensor for the identification of amyloidogenic proteins. Although

157
Q.-h. Shao et al. International Immunopharmacology 49 (2017) 155–160

Fig. 2. Priming and subsequent activation of NLRP3 in-

flammasome by amyloidogenic proteins. The priming
(signal 1) of NLRP3 inflammasome is provided by activating
TLR/NF-κB pathway, leading to the transcription of pro-IL-
1β and pro-IL-18. The phagocytosis of amyloidogenic pro-
teins can induce lysosomal rupture and augment the release
of cathepsin B (signal 2), which contributes to NLRP3, ASC
and caspase-1 protein complex formation. Consequently,
this complex activates caspase-1, generating mature cyto-
kines IL-1β and IL-18.

considerable efforts have been done, our current knowledge about how [4] C.K. Glass, K. Saijo, B. Winner, M.C. Marchetto, F.H. Gage, Mechanisms underlying
inflammation in neurodegeneration, Cell 140 (6) (2010) 918–934.
NLRP3 inflammasome can be activated is not precise. In existing re- [5] L. Du, Y. Zhang, Y. Chen, J. Zhu, Y. Yang, H.L. Zhang, Role of microglia in neu-
sults, it has proved that aggregated amyloid-β and α-synuclein fibrils rological disorders and their potentials as a therapeutic target, Mol. Neurobiol.
could promote the activation of NLRP3 inflammasome via activating (2016).
[6] G. Trendelenburg, Acute neurodegeneration and the inflammasome: central pro-
TLR/NF-κB pathway, inducing lysosomal rupture and cathepsin B re- cessor for danger signals and the inflammatory response? J. Cereb. Blood Flow
lease. There are a series of promising therapeutic measures that target Metab. 28 (5) (2008) 867–881.
the NLRP3 inflammasome signaling including anti-IL-1 therapy, small [7] M. Prinz, J. Priller, S.S. Sisodia, R.M. Ransohoff, Heterogeneity of CNS myeloid cells
and their roles in neurodegeneration, Nat. Neurosci. 14 (10) (2011) 1227–1235.
molecule NLRP3 inhibitors and other compounds. However, a key step [8] R. Patejdl, I.K. Penner, T.K. Noack, U.K. Zettl, Multiple sclerosis and fatigue: a re-
forward is to find out the specific brain regions of inflammasome ac- view on the contribution of inflammation and immune-mediated neurodegenera-
tivation and specific cell types during these diseases. Further in- tion, Autoimmun. Rev. 15 (3) (2016) 210–220.
[9] K.H. Mills, L.S. Dungan, S.A. Jones, J. Harris, The role of inflammasome-derived IL-
vestigation and illumination of the underlying molecular mechanisms
1 in driving IL-17 responses, J. Leukoc. Biol. 93 (4) (2013) 489–497.
about NLRP3 inflammasome activation have a great value. Hence, this [10] M. Lamkanfi, L. Vande Walle, T.D. Kanneganti, Deregulated inflammasome sig-
review highlights that NLRP3 inflammasome therapeutic intervention naling in disease, Immunol. Rev. 243 (1) (2011) 163–173.
can be a potential target for the prevention or treatment of neurode- [11] G. Singhal, E.J. Jaehne, F. Corrigan, C. Toben, B.T. Baune, Inflammasomes in
neuroinflammation and changes in brain function: a focused review, Front.
generative diseases. Neurosci. 8 (2014) 315.
[12] F. Chiti, C.M. Dobson, Protein misfolding, functional amyloid, and human disease,
Conflict of interest Annu. Rev. Biochem. 75 (2006) 333–366.
[13] R. Hanamsagar, M.L. Hanke, T. Kielian, Toll-like receptor (TLR) and inflammasome
actions in the central nervous system, Trends Immunol. 33 (7) (2012) 333–342.
The authors have declared no conflict of interest. [14] M. Margittai, R. Langen, Fibrils with parallel in-register structure constitute a major
class of amyloid fibrils: molecular insights from electron paramagnetic resonance
spectroscopy, Q. Rev. Biophys. 41 (3–4) (2008) 265–297.
Acknowledgments [15] S.L. Masters, L.A. O'Neill, Disease-associated amyloid and misfolded protein ag-
gregates activate the inflammasome, Trends Mol. Med. 17 (5) (2011) 276–282.
This work was supported by Beijing Natural Science Foundation [16] M. Lamkanfi, V.M. Dixit, Mechanisms and functions of inflammasomes, Cell 157 (5)
(2014) 1013–1022.
(NO. 7161011), National Natural Science Foundation of China Grants [17] P.H. Saavedra, D. Demon, H. Van Gorp, M. Lamkanfi, Protective and detrimental
(U1402221, 81573640, 81373997) and the Beijing Key Laboratory of roles of inflammasomes in disease, Semin. Immunopathol. 37 (4) (2015) 313–322.
New Drug Mechanisms and Pharmacological Evaluation Study [18] C.M. Volpe, P.M. Anjos, J.A. Nogueira-Machado, Inflammasome as a new ther-
apeutic target for diabetic complications, Recent Pat. Endocr. Metab. Immune Drug
(BZ0150).
Discov. (2016).
[19] J.C. Reed, K. Doctor, A. Rojas, J.M. Zapata, C. Stehlik, L. Fiorentino, J. Damiano,
References W. Roth, S. Matsuzawa, R. Newman, S. Takayama, H. Marusawa, F. Xu, G. Salvesen,
A. Godzik, Comparative analysis of apoptosis and inflammation genes of mice and
humans, Genome Res. 13 (6b) (2003) 1376–1388.
[1] J. Nagai, R. Baba, T. Ohshima, CRMPs function in neurons and glial cells: potential [20] J.P. Ting, R.C. Lovering, E.S. Alnemri, J. Bertin, J.M. Boss, B.K. Davis, R.A. Flavell,
therapeutic targets for neurodegenerative diseases and CNS injury, Mol. Neurobiol. S.E. Girardin, A. Godzik, J.A. Harton, H.M. Hoffman, J.P. Hugot, N. Inohara,
(2016). A. Mackenzie, L.J. Maltais, G. Nunez, Y. Ogura, L.A. Otten, D. Philpott, J.C. Reed,
[2] J.G. Walsh, D.A. Muruve, C. Power, Inflammasomes in the CNS, Nat. Rev. Neurosci. W. Reith, S. Schreiber, V. Steimle, P.A. Ward, The NLR gene family: a standard
15 (2) (2014) 84–97. nomenclature, Immunity 28 (3) (2008) 285–287.
[3] S.S. Shaftel, W.S. Griffin, M.K. O'Banion, The role of interleukin-1 in neuroin- [21] L.C. Freeman, J.P. Ting, The pathogenic role of the inflammasome in neurode-
flammation and Alzheimer disease: an evolving perspective, J. Neuroinflammation generative diseases, J. Neurochem. 136 (Suppl. 1) (2016) 29–38.
5 (2008) 7. [22] M.R. de Zoete, R.A. Flavell, Interactions between Nod-like receptors and intestinal

158
Q.-h. Shao et al. International Immunopharmacology 49 (2017) 155–160

bacteria, Front. Immunol. 4 (2013) 462. induced by intracerebroventricular infusion of human beta-amyloid, J.
[23] F. Martinon, K. Burns, J. Tschopp, The inflammasome: a molecular platform trig- Neuroinflammation 2 (2005) 15.
gering activation of inflammatory caspases and processing of proIL-beta, Mol. Cell [52] L.A. Joosten, S. Abdollahi-Roodsaz, C.A. Dinarello, L. O'Neill, M.G. Netea, Toll-like
10 (2) (2002) 417–426. receptors and chronic inflammation in rheumatic diseases: new developments, Nat.
[24] E.D. Boyden, W.F. Dietrich, Nalp1b controls mouse macrophage susceptibility to Rev. Rheumatol. 12 (6) (2016) 344–357.
anthrax lethal toxin, Nat. Genet. 38 (2) (2006) 240–244. [53] M.G. Netea, F.L. van de Veerdonk, J.W. van der Meer, C.A. Dinarello, L.A. Joosten,
[25] S.B. Liu, W.L. Mi, Y.Q. Wang, Research progress on the NLRP3 inflammasome and Inflammasome-independent regulation of IL-1-family cytokines, Annu. Rev.
its role in the central nervous system, Neurosci. Bull. 29 (6) (2013) 779–787. Immunol. 33 (2015) 49–77.
[26] F.S. Sutterwala, R.A. Flavell, NLRC4/IPAF: a CARD carrying member of the NLR [54] S.M. Man, T.D. Kanneganti, Regulation of inflammasome activation, Immunol. Rev.
family, Clin. Immunol. 130 (1) (2009) 2–6. 265 (1) (2015) 6–21.
[27] M. Wlodarska, C.A. Thaiss, R. Nowarski, J. Henao-Mejia, J.P. Zhang, E.M. Brown, [55] M.R. de Zoete, N.W. Palm, S. Zhu, R.A. Flavell, Inflammasomes, Cold Spring Harb.
G. Frankel, M. Levy, M.N. Katz, W.M. Philbrick, E. Elinav, B.B. Finlay, R.A. Flavell, Perspect. Biol. 6 (12) (2014) a016287.
NLRP6 inflammasome orchestrates the colonic host-microbial interface by reg- [56] H. Hong, B.S. Kim, H.I. Im, Pathophysiological role of neuroinflammation in neu-
ulating goblet cell mucus secretion, Cell 156 (5) (2014) 1045–1059. rodegenerative diseases and psychiatric disorders, Int. Neurourol. J. 20 (Suppl. 1)
[28] S. Khare, A. Dorfleutner, N.B. Bryan, C. Yun, A.D. Radian, L. de Almeida, (2016) S2–S7.
Y. Rojanasakul, C. Stehlik, An NLRP7-containing inflammasome mediates re- [57] M.L. Block, J.S. Hong, Microglia and inflammation-mediated neurodegeneration:
cognition of microbial lipopeptides in human macrophages, Immunity 36 (3) multiple triggers with a common mechanism, Prog. Neurobiol. 76 (2) (2005) 77–98.
(2012) 464–476. [58] A. Wimo, L. Jonsson, B. Winblad, An estimate of the worldwide prevalence and
[29] S.M. Man, R. Karki, T.D. Kanneganti, AIM2 inflammasome in infection, cancer, and direct costs of dementia in 2003, Dement. Geriatr. Cogn. Disord. 21 (3) (2006)
autoimmunity: role in DNA sensing, inflammation, and innate immunity, Eur. J. 175–181.
Immunol. 46 (2) (2016) 269–280. [59] C.L. Masters, D.J. Selkoe, Biochemistry of amyloid beta-protein and amyloid de-
[30] M. Keller, A. Ruegg, S. Werner, H.D. Beer, Active caspase-1 is a regulator of un- posits in Alzheimer disease, Cold Spring Harb. Perspect. Med. 2 (6) (2012)
conventional protein secretion, Cell 132 (5) (2008) 818–831. a006262.
[31] E.K. Jo, J.K. Kim, D.M. Shin, C. Sasakawa, Molecular mechanisms regulating NLRP3 [60] M.I. Aguilar, D.H. Small, Surface plasmon resonance for the analysis of beta-amy-
inflammasome activation, Cell Mol. Immunol. 13 (2) (2016) 148–159. loid interactions and fibril formation in Alzheimer's disease research, Neurotox. Res.
[32] S. Mariathasan, D.S. Weiss, K. Newton, J. McBride, K. O'Rourke, M. Roose-Girma, 7 (1–2) (2005) 17–27.
W.P. Lee, Y. Weinrauch, D.M. Monack, V.M. Dixit, Cryopyrin activates the in- [61] K. Morimoto, J. Horio, H. Satoh, L. Sue, T. Beach, S. Arita, I. Tooyama, Y. Konishi,
flammasome in response to toxins and ATP, Nature 440 (7081) (2006) 228–232. Expression profiles of cytokines in the brains of Alzheimer's disease (AD) patients
[33] I.C. Allen, M.A. Scull, C.B. Moore, E.K. Holl, E. McElvania-TeKippe, D.J. Taxman, compared to the brains of non-demented patients with and without increasing AD
E.H. Guthrie, R.J. Pickles, J.P. Ting, The NLRP3 inflammasome mediates in vivo pathology, J. Alzheimers Dis. 25 (1) (2011) 59–76.
innate immunity to influenza A virus through recognition of viral RNA, Immunity [62] J.M. Rubio-Perez, J.M. Morillas-Ruiz, A review: inflammatory process in
30 (4) (2009) 556–565. Alzheimer's disease, role of cytokines, ScientificWorldJournal 2012 (2012) 756357.
[34] S. Joly, N. Ma, J.J. Sadler, D.R. Soll, S.L. Cassel, F.S. Sutterwala, Cutting edge: [63] C. Cunningham, Microglia and neurodegeneration: the role of systemic inflamma-
Candida albicans hyphae formation triggers activation of the Nlrp3 inflammasome, tion, Glia 61 (1) (2013) 71–90.
J. Immunol. 183 (6) (2009) 3578–3581. [64] J.E. Lim, J. Kou, M. Song, A. Pattanayak, J. Jin, R. Lalonde, K. Fukuchi, MyD88
[35] M. Karmakar, M.A. Katsnelson, G.R. Dubyak, Neutrophil P2X7 Receptors Mediate deficiency ameliorates beta-amyloidosis in an animal model of Alzheimer's disease,
NLRP3 Inflammasome-dependent IL-1beta Secretion in Response to ATP, 7 (2016), Am. J. Pathol. 179 (3) (2011) 1095–1103.
p. 10555. [65] G.J. Rapsinski, M.A. Wynosky-Dolfi, G.O. Oppong, S.A. Tursi, R.P. Wilson,
[36] P. Duewell, H. Kono, K.J. Rayner, C.M. Sirois, G. Vladimer, F.G. Bauernfeind, I.E. Brodsky, C. Tukel, Toll-like receptor 2 and NLRP3 cooperate to recognize a
G.S. Abela, L. Franchi, G. Nunez, M. Schnurr, T. Espevik, E. Lien, K.A. Fitzgerald, functional bacterial amyloid, curli, Infect. Immun. 83 (2) (2015) 693–701.
K.L. Rock, K.J. Moore, S.D. Wright, V. Hornung, E. Latz, NLRP3 inflammasomes are [66] T. Wyss-Coray, J. Rogers, Inflammation in Alzheimer disease—a brief review of the
required for atherogenesis and activated by cholesterol crystals, Nature 464 (7293) basic science and clinical literature, Cold Spring Harb. Perspect. Med. 2 (1) (2012)
(2010) 1357–1361. a006346.
[37] A. Halle, V. Hornung, G.C. Petzold, C.R. Stewart, B.G. Monks, T. Reinheckel, [67] F.J. Sheedy, A. Grebe, K.J. Rayner, P. Kalantari, B. Ramkhelawon, S.B. Carpenter,
K.A. Fitzgerald, E. Latz, K.J. Moore, D.T. Golenbock, The NALP3 inflammasome is C.E. Becker, H.N. Ediriweera, A.E. Mullick, D.T. Golenbock, L.M. Stuart, E. Latz,
involved in the innate immune response to amyloid-beta, Nat. Immunol. 9 (8) K.A. Fitzgerald, K.J. Moore, CD36 coordinates NLRP3 inflammasome activation by
(2008) 857–865. facilitating intracellular nucleation of soluble ligands into particulate ligands in
[38] E.I. Elliott, F.S. Sutterwala, Initiation and perpetuation of NLRP3 inflammasome sterile inflammation, Nat. Immunol. 14 (8) (2013) 812–820.
activation and assembly, Immunol. Rev. 265 (1) (2015) 35–52. [68] M.T. Heneka, M.P. Kummer, A. Stutz, A. Delekate, S. Schwartz, A. Vieira-Saecker,
[39] T. Murakami, J. Ockinger, J. Yu, V. Byles, A. McColl, A.M. Hofer, T. Horng, Critical A. Griep, D. Axt, A. Remus, T.C. Tzeng, E. Gelpi, A. Halle, M. Korte, E. Latz,
role for calcium mobilization in activation of the NLRP3 inflammasome, Proc. Natl. D.T. Golenbock, NLRP3 is activated in Alzheimer's disease and contributes to pa-
Acad. Sci. U. S. A. 109 (28) (2012) 11282–11287. thology in APP/PS1 mice, Nature 493 (7434) (2013) 674–678.
[40] M. Lamkanfi, V.M. Dixit, Inflammasomes: guardians of cytosolic sanctity, Immunol. [69] J.Q. Shi, C.C. Zhang, X.L. Sun, X.X. Cheng, J.B. Wang, Y.D. Zhang, J. Xu, H.Q. Zou,
Rev. 227 (1) (2009) 95–105. Antimalarial drug artemisinin extenuates amyloidogenesis and neuroinflammation
[41] J. Tschopp, K. Schroder, NLRP3 inflammasome activation: the convergence of in APPswe/PS1dE9 transgenic mice via inhibition of nuclear factor-kappaB and
multiple signalling pathways on ROS production? Nat. Rev. Immunol. 10 (3) (2010) NLRP3 inflammasome activation, CNS Neurosci. Ther. 19 (4) (2013) 262–268.
210–215. [70] M. Schnaars, H. Beckert, A. Halle, Assessing beta-amyloid-induced NLRP3 in-
[42] C. Jin, P. Frayssinet, R. Pelker, D. Cwirka, B. Hu, A. Vignery, S.C. Eisenbarth, flammasome activation in primary microglia, Methods Mol. Biol. 1040 (2013) 1–8.
R.A. Flavell, NLRP3 inflammasome plays a critical role in the pathogenesis of hy- [71] V. Hornung, E. Latz, Critical functions of priming and lysosomal damage for NLRP3
droxyapatite-associated arthropathy, Proc. Natl. Acad. Sci. U. S. A. 108 (36) (2011) activation, Eur. J. Immunol. 40 (3) (2010) 620–623.
14867–14872. [72] I. Hafner-Bratkovic, M. Bencina, K.A. Fitzgerald, D. Golenbock, R. Jerala, NLRP3
[43] Y. Yin, Y. Yan, X. Jiang, J. Mai, N.C. Chen, H. Wang, X.F. Yang, Inflammasomes are inflammasome activation in macrophage cell lines by prion protein fibrils as the
differentially expressed in cardiovascular and other tissues, Int. J. Immunopathol. source of IL-1beta and neuronal toxicity, Cell. Mol. Life Sci. 69 (24) (2012)
Pharmacol. 22 (2) (2009) 311–322. 4215–4228.
[44] A. Gustin, M. Kirchmeyer, E. Koncina, P. Felten, S. Losciuto, T. Heurtaux, [73] M.S. Tan, J.T. Yu, T. Jiang, X.C. Zhu, L. Tan, The NLRP3 inflammasome in
A. Tardivel, P. Heuschling, C. Dostert, NLRP3 inflammasome is expressed and Alzheimer's disease, Mol. Neurobiol. 48 (3) (2013) 875–882.
functional in mouse brain microglia but not in astrocytes, PLoS One 10 (6) (2015) [74] K. Schroder, J. Tschopp, The inflammasomes, Cell 140 (6) (2010) 821–832.
e0130624. [75] S. Mueller-Steiner, Y. Zhou, H. Arai, E.D. Roberson, B. Sun, J. Chen, X. Wang, G. Yu,
[45] S.E. Terrill-Usery, M.J. Mohan, M.R. Nichols, Amyloid-beta(1-42) protofibrils sti- L. Esposito, L. Mucke, L. Gan, Antiamyloidogenic and neuroprotective functions of
mulate a quantum of secreted IL-1beta despite significant intracellular IL-1beta cathepsin B: implications for Alzheimer's disease, Neuron 51 (6) (2006) 703–714.
accumulation in microglia, Biochim. Biophys. Acta 1842 (11) (2014) 2276–2285. [76] V.Y. Hook, M. Kindy, G. Hook, Inhibitors of cathepsin B improve memory and re-
[46] G. Codolo, N. Plotegher, T. Pozzobon, M. Brucale, I. Tessari, L. Bubacco, M. de duce beta-amyloid in transgenic Alzheimer disease mice expressing the wild-type,
Bernard, Triggering of inflammasome by aggregated alpha-synuclein, an in- but not the Swedish mutant, beta-secretase site of the amyloid precursor protein, J.
flammatory response in synucleinopathies, PLoS One 8 (1) (2013) e55375. Biol. Chem. 283 (12) (2008) 7745–7753.
[47] L. Steinman, Inflammatory cytokines at the summits of pathological signal cascades [77] N. Murphy, B. Grehan, M.A. Lynch, Glial uptake of amyloid beta induces NLRP3
in brain diseases, Sci. Signal 6 (258) (2013) pe3. inflammasome formation via cathepsin-dependent degradation of NLRP10,
[48] S.M. Allan, P.J. Tyrrell, N.J. Rothwell, Interleukin-1 and neuronal injury, Nat. Rev. NeuroMolecular Med. 16 (1) (2014) 205–215.
Immunol. 5 (8) (2005) 629–640. [78] M.H. Cho, K. Cho, H.J. Kang, E.Y. Jeon, H.S. Kim, H.J. Kwon, H.M. Kim, D.H. Kim,
[49] J.A. Smith, A. Das, S.K. Ray, N.L. Banik, Role of pro-inflammatory cytokines re- S.Y. Yoon, Autophagy in microglia degrades extracellular beta-amyloid fibrils and
leased from microglia in neurodegenerative diseases, Brain Res. Bull. 87 (1) (2012) regulates the NLRP3 inflammasome, Autophagy 10 (10) (2014) 1761–1775.
10–20. [79] R. Abdullah, I. Basak, K.S. Patil, G. Alves, J.P. Larsen, S.G. Moller, Parkinson's
[50] S. Tanaka, A. Ishii, H. Ohtaki, S. Shioda, T. Yoshida, S. Numazawa, Activation of disease and age: the obvious but largely unexplored link, Exp. Gerontol. 68 (2015)
microglia induces symptoms of Parkinson's disease in wild-type, but not in IL-1 33–38.
knockout mice, J. Neuroinflammation 10 (2013) 143. [80] I. Stojkovska, B.M. Wagner, B.E. Morrison, Parkinson's disease and enhanced in-
[51] J.M. Craft, D.M. Watterson, E. Hirsch, L.J. Van Eldik, Interleukin 1 receptor an- flammatory response, Exp. Biol. Med. (Maywood) 240 (11) (2015) 1387–1395.
tagonist knockout mice show enhanced microglial activation and neuronal damage [81] E.C. Hirsch, T. Breidert, E. Rousselet, S. Hunot, A. Hartmann, P.P. Michel, The role

159
Q.-h. Shao et al. International Immunopharmacology 49 (2017) 155–160

of glial reaction and inflammation in Parkinson's disease, Ann. N. Y. Acad. Sci. 991 Inflamm. 2013 (2013) 952375.
(2003) 214–228. [90] A. Gustot, J.I. Gallea, R. Sarroukh, M.S. Celej, J.M. Ruysschaert, V. Raussens,
[82] C.C. Ferrari, M.C. Pott Godoy, R. Tarelli, M. Chertoff, A.M. Depino, F.J. Pitossi, Amyloid fibrils are the molecular trigger of inflammation in Parkinson's disease,
Progressive neurodegeneration and motor disabilities induced by chronic expres- Biochem. J. 471 (3) (2015) 323–333.
sion of IL-1beta in the substantia nigra, Neurobiol. Dis. 24 (1) (2006) 183–193. [91] Z. Fan, M. Lu, C. Qiao, Y. Zhou, J.H. Ding, G. Hu, MicroRNA-7 enhances sub-
[83] M.C. Pott Godoy, R. Tarelli, C.C. Ferrari, M.I. Sarchi, F.J. Pitossi, Central and sys- ventricular zone neurogenesis by inhibiting NLRP3/caspase-1 axis in adult neural
temic IL-1 exacerbates neurodegeneration and motor symptoms in a model of stem cells, Mol. Neurobiol. (2015).
Parkinson's disease, Brain 131 (Pt 7) (2008) 1880–1894. [92] H.L. Roberts, D.R. Brown, Seeking a mechanism for the toxicity of oligomeric alpha-
[84] M.T. Herrero, C. Estrada, L. Maatouk, S. Vyas, Inflammation in Parkinson's disease: synuclein, Biomol. Ther. 5 (2) (2015) 282–305.
role of glucocorticoids, Front. Neuroanat. 9 (2015) 32. [93] Y. Zhou, M. Lu, R.H. Du, C. Qiao, C.Y. Jiang, K.Z. Zhang, J.H. Ding, G. Hu,
[85] L. Alvarez-Erviti, Y. Couch, J. Richardson, J.M. Cooper, M.J. Wood, Alpha-synuclein MicroRNA-7 targets Nod-like receptor protein 3 inflammasome to modulate neu-
release by neurons activates the inflammatory response in a microglial cell line, roinflammation in the pathogenesis of Parkinson's disease, Mol. Neurodegener. 11
Neurosci. Res. 69 (4) (2011) 337–342. (2016) 28.
[86] B. Winner, R. Jappelli, S.K. Maji, P.A. Desplats, L. Boyer, S. Aigner, C. Hetzer, [94] H.J. Lee, S. Patel, S.J. Lee, Intravesicular localization and exocytosis of alpha-sy-
T. Loher, M. Vilar, S. Campioni, C. Tzitzilonis, A. Soragni, S. Jessberger, H. Mira, nuclein and its aggregates, J. Neurosci. 25 (25) (2005) 6016–6024.
A. Consiglio, E. Pham, E. Masliah, F.H. Gage, R. Riek, In vivo demonstration that [95] F. Martinon, Signaling by ROS drives inflammasome activation, Eur. J. Immunol. 40
alpha-synuclein oligomers are toxic, Proc. Natl. Acad. Sci. U. S. A. 108 (10) (2011) (3) (2010) 616–619.
4194–4199. [96] D. Freeman, R. Cedillos, S. Choyke, Z. Lukic, K. McGuire, S. Marvin, A.M. Burrage,
[87] C.W. Olanow, P. Brundin, Parkinson's disease and alpha synuclein: is Parkinson's S. Sudholt, A. Rana, C. O'Connor, C.M. Wiethoff, E.M. Campbell, Alpha-synuclein
disease a prion-like disorder? Mov. Disord. 28 (1) (2013) 31–40. induces lysosomal rupture and cathepsin dependent reactive oxygen species fol-
[88] D. Litteljohn, E. Mangano, M. Clarke, J. Bobyn, K. Moloney, S. Hayley, lowing endocytosis, PLoS One 8 (4) (2013) e62143.
Inflammatory mechanisms of neurodegeneration in toxin-based models of [97] F. Shi, Y. Yang, M. Kouadir, Y. Fu, L. Yang, X. Zhou, X. Yin, D. Zhao, Inhibition of
Parkinson's disease, Park. Dis. 2011 (2010) 713517. phagocytosis and lysosomal acidification suppresses neurotoxic prion peptide-in-
[89] S.V. More, H. Kumar, I.S. Kim, S.Y. Song, D.K. Choi, Cellular and molecular med- duced NALP3 inflammasome activation in BV2 microglia, J. Neuroimmunol. 260
iators of neuroinflammation in the pathogenesis of Parkinson's disease, Mediat. (1–2) (2013) 121–125.

160