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The Function of NOD-Like Receptors in Central Nervous System Diseases

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The Function of NOD-Like Receptors in Central Nervous System Diseases Journal of Neuroscience Research 95:1565–1573 (2017) Review The Function of NOD-like Receptors in Central Nervous System Diseases Xiangxi Kong,1,2 Zengqiang Yuan,1,3* and Jinbo Cheng1,3* 1The State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China 2School of Basic Medical Science, Lanzhou University, Lanzhou 730000, Gansu Province, China 3Center of Alzheimer’s Disease, Beijing Institute for Brain Disorders, Beijing 100069, China NOD-like receptors (NLRs) are critical cytoplasmic domain for ligand recognition and a cytoplasmic domain pattern-recognition receptors (PRRs) that play an impor- for signal transduction, whereas RLRs are cytosolic tant role in the host innate immune response and immu- receptors that respond to viral infections and maintain nity homeostasis. There is a growing body of evidence immune homeostasis (Kawai et al., 2005; Rehwinkel and that NLRs are involved in a wide range of inflammatory Reis e Sousa 2010; Seth et al., 2005; Xu et al., 2005). diseases, including cancer, metabolic diseases, and NLRs are also cytosolic sensors, which contain a autoimmune disorders. Recent studies have indicated NACHT domain and a C-terminal leucine-rich repeat that the proteins of the NLR family are linked with the (LRR) domain. More than twenty members of the NLR pathophysiology of neurodegenerative diseases, includ- family of receptors have been identified and can be divid- ing Alzheimer’s disease (AD), Parkinson’s disease (PD), ed into four subfamilies on the basis of their different N- and multiple sclerosis (MS), and psychological diseases. terminal regions (Figure 1): NLRA, which consists of a In this review, we mainly focus on the role of NLRs and class II transactivator (CIITA); NLRB, which consists of a the underlying signaling pathways in central nervous sys- neural apoptosis inhibitory protein (NAIP); NLRC, tem (CNS) diseases. VC 2016 Wiley Periodicals, Inc. which consists of NOD1, NOD2, NLRC3–NLRC5, Key words: NOD-like receptors; innate immunity; neuro- and NLRX1; and NLRP, which consists of NLRP1- degeneration; neuroinflammation; inflammasome SIGNIFICANCE INTRODUCTION NOD-like receptors (NLRs) play important roles in the host innate immune response and immunity homeostasis. In this review, we sum- Innate immunity represents one of the first lines of marized the role of the NLR family of proteins and the mechanism defense against intracellular and extracellular signals (Ath- of signaling regulation in neurodegenerative diseases, including Alz- man and Philpott 2004; Carneiro et al., 2007; Cheng heimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis et al., 2016a; Matsushima et al., 2015). Many cells contrib- (MS), and psychological diseases. We believe that targeting NLR pro- ute to the innate immune system, including macrophages, teins in the future will be a new therapeutic strategy for the treatment dendritic cells (DCs), epithelial cells, and endothelial cells of related neurological diseases. in the peripheral immune system. In the brain, although microglia are the main innate immune cells, astrocytes, oligodendrocytes, and neurons are also involved in neuro- This work was supported by grants from the National Nature Science nal innate immunity. Germ-line-encoded pattern-recog- Foundation of China (81125010, 81030025, 81400987, 81230026) and nition receptors (PRRs) are responsible for the activation the Beijing Nature Science Foundation (7132147). of innate immunity (Davis et al., 2011), which recognize *Correspondence to: Jinbo Cheng, PhD, State Key Laboratory of Brain two types of molecules: pathogen-associated molecular and Cognitive Sciences, Institute of Biophysics, Chinese Academy of patterns (PAMPs) and damage-associated molecular pat- Sciences, Beijing 100101, China. Email: [email protected]; and terns (DAMPs) (Basset et al., 2003; Martinon et al., 2009). Zengqiang Yuan, PhD, State Key Laboratory of Brain and Cognitive Sci- PRRs can be divided into four groups on the basis ences, Institute of Biophysics, Chinese Academy of Sciences, Beijing of their different structures and functions, namely toll-like 100101, China. Email: [email protected] receptors (TLRs), retinoid acid-inducible gene-1 (RIG- Received 12 July 2016; Revised 11 November 2016; Accepted 28 1)-like receptors (RLRs), C-type lectin receptors (CLRs), November 2016 and NOD-like receptors (NLRs). TLRs act as a vanguard Published online 28 December 2016 in Wiley Online Library in the host immune system, and have an extra membrane (wileyonlinelibrary.com). DOI: 10.1002/jnr.24004 VC 2016 Wiley Periodicals, Inc. 1566 Kong et al. Fig. 1. NOD-like receptors (NLRs) can be divided into four groups: NLRA, which consists of a class II transactivator (CIITA); NLRB, which consists of a neural apoptosis inhibitory protein (NAIP); NLRC, which consists of NOD1, NOD2, NLRC3–NLRC5, and NLRX1; and NLRP, which con- sists of NLRP1–NLRP14. NLRP14. CIITA plays a role in tumor suppression (Lee protein containing a CARD (ASC), caspase-1, and et al., 2011). NOD1 and NOD2 are cytoplasmic proteins NAIP, which sequentially leads to the release of IL-1b that lack transmembrane domains. However, these pro- and IL-18 (Lage et al., 2014). The formation of this com- teins can be recruited to the plasma membrane where plex can suppress bacterial replication during the initial they regulate nuclear factor kappa-light-chain-enhancer time of infection. NLRC5 modulates inflammatory of activated B cells (NF-jB) signaling and the mitogen- responses by regulating the expression of MHC class I and activated protein kinase (MAPK) pathway (Philpott et al., class II proteins (Meissner et al., 2010). NLRX1 seques- 2014). Mutations in NOD1 and NOD2 have been associ- ters STING for the negative regulation of interferon ated with Crohn’s disease (CD) and other inflammatory secretion, which facilitates the replication of viruses (Guo bowel disorders (Correa et al., 2012), which suggests that et al., 2016). In addition, NLRX1 promotes dynamin- NOD1 and NOD2 play an important role in maintaining related protein-1 (DRP1) phosphorylation and increases gut homeostasis. Furthermore, NOD2 interacts with mitochondrial fission, which changes the cell fate from mitochondrial antiviral signaling protein (MAVS) (Lupfer necrosis to apoptosis (Imbeault et al., 2014). and Kanneganti, 2013a), which might be essential for the NLRP1 was the first member of the NLR family of production of IFN-b to suppress virus replication during proteins to be identified. Once activated, NLRP1 specifi- viral infections. NLRC3 attenuates toll-like receptor sig- cally recruits and activates caspase-1 downstream, which naling through modification of the signaling adaptor TNF subsequently cleaves pro-IL-1b and pro-IL-18 and pro- receptor-associated factor 6 (TRAF6), the transcription motes the maturation and release of IL-1b and IL-18 factor NF-jB, and the DNA sensor stimulator of type I (Martinon et al., 2002). Several lines of evidence show IFN gene (STING) (Mangan and Latz, 2014; Schneider that NLRP2, NLRP4, NLRP5, and NLRP7 play impor- et al., 2012). NLRC4 is activated by bacterial flagellin or tant roles in embryonic development (Bauernfeind et al., the rod complex of bacterial type III secretion systems 2009; Murdoch et al., 2006; Peng et al., 2015; Zhang (T3SS) (Amer et al., 2006). Once activated, NLRC4 et al., 2008). NLRP3 is the most-studied member of the forms a multimeric complex, called an inflammasome, NLR family of proteins. NLRP3 responds to a panel of containing the adaptor apoptosis-associated speck-like PAMPs and DAMPs, including bacterial messenger Journal of Neuroscience Research NLRs in the CNS Diseases 1567 TABLE I. The Expression Levels of NLRs in the Brain Cell type in the brain Newly formed Myelinating Gene Name Astrocyte Neuron OPC Oligodendrocyte Oligodendrocyte Microglia Endothelial CIITA 111 1 1 1 1 NAIP - - - - - - - NOD1 1** 1** 11** 1*** 1*** 1*** NOD2 111 1 1 1** 1* NLRC3 111 1 1 1 1** NLRC4 111 1 1 1 1 NLRC5 111 1 1 1 1 NLRX1 1** 1** 1** 1* 1** 1** 1* NLRP1 - - - - - - - NLRP2 111 1 1 1 1 NLRP3 - - 1** - - 1*** - NLRP4 - - - - - - - NLRP5 111 1 1 1 1 NLRP6 111 1 1 1 1 NLRP7 - - - - - - - NLRP8 - - - - - - - NLRP9 - - - - - - - NLRP10 111 1 1 1 1 NLRP11 - - - - - - - NLRP12 111 1 1 1 1 NLRP13 - - - - - - - NLRP14 111 1 1 1 1 An expression level of 0.5 < FPKM 1.0 was indicated as “*”; 1.0 < FPKM 5.0 was indicated as “**”; FPKM 5.0 was indicated as “***” (FPKM: fragments per kilobase of transcript sequence per million mapped fragments). RNA, muramyl dipeptide (MDP), DNA and RNA virus- review, we mainly focus on the NLRs related to nervous es, fungi, protozoa, ATP, uric acid crystals, silica, alumi- system diseases. num hydroxide, LPS, PM10 particles, and Ca21 ions (Lupfer and Kanneganti 2013b; Martinon et al., 2006). The Expression of NLRs in the Brain The activation of the NLRP3 inflammasome requires Although NLRs play an important role in innate two steps. The first step is a priming step, e.g., the immunity, there has been limited study of the expression increased expression of NLRP3, which is induced by the of NLRs in the brain and this topic has been rarely activation of toll-like receptor 2, toll-like receptor 4, reviewed. We used the data held in an RNA-Seq tran- NOD2-, TNFR1-, or TNFR2-mediated NF-jB signal- scriptome and splicing database of glia, neurons, and vas- ing. The second step is the activation step, which is trig- cular cells of the cerebral cortex (Zhang et al., 2014a) to gered by a PAMP or DAMP and leads to inflammasome summarize the expression pattern of all the proteins of the assembly, IL-1b and IL-18 release, and pyroptosis (Man NLR family in the brain. As shown in Table I, only and Kanneganti 2015). During the activation step, NOD1 and NLRX1 are highly expressed in all cell types caspase-1, caspase-11, caspase-4, caspase-5, and caspase- in the brain, including astrocytes, neurons, OPCs, newly 8 participate in the activation of the NLRP3 inflamma- formed oligodendrocytes, myelinating oligodendrocytes, some (Antonopoulos et al., 2015; Baker et al., 2015; microglia, and endothelial cells.
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