The function of NOD‐like receptors in central nervous system diseases

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Innate immunity represents one of the first lines of defense against intracellular and extracellular signals (Athman and Philpott 2004; Carneiro et al., 2007; Cheng et al., 2016a; Matsushima et al., 2015). Many cells contribute to the innate immune system, including macrophages, dendritic cells (DCs), epithelial cells, and endothelial cells in the peripheral immune system. In the brain, although microglia are the main innate immune cells, astrocytes, oligodendrocytes, and neurons are also involved in neuronal innate immunity. Germ‐line‐encoded pattern‐recognition receptors (PRRs) are responsible for the activation of innate immunity (Davis et al., 2011), which recognize two types of molecules: pathogen‐associated molecular patterns (PAMPs) and damage‐associated molecular patterns (DAMPs) (Basset et al., 2003; Martinon et al., 2009).
PRRs can be divided into four groups on the basis of their different structures and functions, namely toll‐like receptors (TLRs), retinoid acid‐inducible gene‐1 (RIG‐1)‐like receptors (RLRs), C‐type lectin receptors (CLRs), and NOD‐like receptors (NLRs). TLRs act as a vanguard in the host immune system, and have an extra membrane domain for ligand recognition and a cytoplasmic domain for signal transduction, whereas RLRs are cytosolic receptors that respond to viral infections and maintain immune homeostasis (Kawai et al., 2005; Rehwinkel and Reis e Sousa 2010; Seth et al., 2005; Xu et al., 2005). NLRs are also cytosolic sensors, which contain a NACHT domain and a C‐terminal leucine‐rich repeat (LRR) domain. More than twenty members of the NLR family of receptors have been identified and can be divided into four subfamilies on the basis of their different N‐terminal regions (Figure 1): 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 consists of NLRP1‐NLRP14. CIITA plays a role in tumor suppression (Lee et al., 2011). NOD1 and NOD2 are cytoplasmic proteins that lack transmembrane domains. However, these proteins can be recruited to the plasma membrane where they regulate nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) signaling and the mitogen‐activated protein kinase (MAPK) pathway (Philpott et al., 2014). Mutations in NOD1 and NOD2 have been associated with Crohn's disease (CD) and other inflammatory bowel disorders (Correa et al., 2012), which suggests that NOD1 and NOD2 play an important role in maintaining gut homeostasis. Furthermore, NOD2 interacts with mitochondrial antiviral signaling protein (MAVS) (Lupfer and Kanneganti, 2013a), which might be essential for the production of IFN‐β to suppress virus replication during viral infections. NLRC3 attenuates toll‐like receptor signaling through modification of the signaling adaptor TNF receptor‐associated factor 6 (TRAF6), the transcription factor NF‐κB, and the DNA sensor stimulator of type I IFN gene (STING) (Mangan and Latz, 2014; Schneider et al., 2012). NLRC4 is activated by bacterial flagellin or the rod complex of bacterial type III secretion systems (T3SS) (Amer et al., 2006). Once activated, NLRC4 forms a multimeric complex, called an inflammasome, containing the adaptor apoptosis‐associated speck‐like protein containing a CARD (ASC), caspase‐1, and NAIP, which sequentially leads to the release of IL‐1β and IL‐18 (Lage et al., 2014). The formation of this complex can suppress bacterial replication during the initial time of infection. NLRC5 modulates inflammatory responses by regulating the expression of MHC class I and class II proteins (Meissner et al., 2010). NLRX1 sequesters STING for the negative regulation of interferon secretion, which facilitates the replication of viruses (Guo et al., 2016). In addition, NLRX1 promotes dynamin‐related protein‐1 (DRP1) phosphorylation and increases mitochondrial fission, which changes the cell fate from necrosis to apoptosis (Imbeault et al., 2014).
NLRP1 was the first member of the NLR family of proteins to be identified.
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