Nod Proteins Regulators Of Inflammation In Health And Disease Pdf
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- The Ubiquitin Code of NODs Signaling Pathways in Health and Disease
- NOD2 and inflammation: current insights
- NOD-Like Receptors: Master Regulators of Inflammation and Cancer
- The Role of Innate Immunity Receptors in the Pathogenesis of Inflammatory Bowel Disease
The Ubiquitin Code of NODs Signaling Pathways in Health and Disease
Innate immunity constitutes the first line of defense, fundamental for the recognition and the initiation of an inflammatory response against microorganisms. The innate immune response relies on the sensing of microbial-associated molecular patterns through specialized structures such as toll-like receptors TLRs and the nucleotide oligomerization domain- NOD- like receptors NLRs. In the gut, these tasks are performed by the epithelial barrier and the presence of adaptive and innate immune mechanisms.
TLRs and NLRs are distributed throughout the gastrointestinal mucosa, being more expressed in the epithelium, and in lamina propria immune and nonimmune cells. These innate immunity receptors exhibit complementary biological functions, with evidence for pathways overlapping.
However, as tolerance is the predominant physiological response in the gastrointestinal mucosa, it appears that the TLRs are relatively downregulated, while NLRs play a critical role in mucosal defense in the gut. Over the past two decades, genetic polymorphisms have been associated with several diseases including inflammatory bowel disease. Nevertheless, the mechanisms underlying innate immune receptors dysfunction that result in the persistent inflammation in inflammatory bowel disease remain to be clarified.
In the gastrointestinal system, homeostasis represents a rather complex and dynamic process, with a critical role for mucosal immunity.
In physiological conditions, it is expected that the host identifies and responds appropriately to the luminal contents of the gastrointestinal tract. In this regard, the epithelium, constituted by a single cell lining, plays an important role separating an essentially sterile internal milieu from a formidable burden of microbes that populate the gastrointestinal tract [ 1 ]. In conjunction with the epithelium, the intestinal immune system also has a critical challenge of distinguishing commensal from pathogenic microorganisms, in a complex and yet incompletely understood mechanism [ 2 ].
The interaction between the gut and the microorganisms that constitute the resident microbiota is tightly regulated and has evolved in the course of several million years [ 3 ]. In fact, this mutualistic relationship between host and microbiota is thought to be essential for the immune homeostasis and is well balanced in normal conditions [ 4 , 5 ]. In this paper, we are going to present an overview of the basic mechanisms of the innate immunity and the defects associated with the development of IBD.
The innate immune system represents the first line of defense against invading microorganisms and is critically important in the early recognition and subsequent initiation of an inflammatory response [ 9 ]. In contrast to the adaptive immunity, the response mounted by the innate immune system has been regarded as relatively nonspecific, being mediated primarily by macrophages, dendritic cells, and granulocytes, basically functioning as phagocytes and antigen presenting cells [ 10 ].
The innate immune response depends on the recognition of evolutionarily conserved structures expressed on microbes, the microbial-associated molecular patterns MAMPs , through special cell receptors. In order to control the number and composition of microbial populations and also to identify potential pathogens, the host needs to maintain surveillance over the microbiota. In the gastrointestinal tract, these tasks are performed by the epithelial barrier and the presence of adaptive and innate immune mechanisms [ 11 , 12 ] Figure 1.
Interactions of the epithelium and other innate immunity cells with microbes are mediated by the presence of transmembrane or cytosolic receptors, called pattern recognition receptors PRRs , capable of sensing and recognizing specific microbial compounds known as MAMPs [ 13 ].
In fact, not only whole microbes, but also diffusible components can interact with the PRRs. Among these receptors, the NOD-like receptors NLRs protect the intracellular cytosolic compartment, while the transmembrane toll-like receptors TLRs survey the extracellular space [ 14 ].
Upon MAMPs recognition, these innate receptors recruit adaptor proteins and cellular kinases, which in turn trigger distinct intracellular signaling cascades, culminating in the activation of the MAPK and NF-kappa B pathways [ 14 , 15 ] Figure 2.
Currently, the TLR family is the best characterized in mammals and is composed of 13 receptors [ 11 ]. For example, lipopolysaccharide internalization was shown to be required for chemokine induction, supporting the idea that NF-kappa B activation might depend upon intracellular TLR4 signaling within the epithelium [ 16 ]. In the human gastrointestinal tract, most TLRs have been shown to be present, with some particularities in terms of distribution and function [ 17 ].
TLR5 is basically expressed in the colonic epithelium and recognizes invasive flagellated bacteria, while TLR2 and TLR4 are present in low levels in the intestinal epithelium, more abundantly in the colonic crypts [ 18 ]. On the other hand, TLR3 appears to be predominantly expressed in mature enterocytes in both the small bowel and the colon [ 14 , 19 ]. Interestingly, in regard to TLR9 in the intestinal epithelium, it has been demonstrated that activation through the apical membrane determines tolerance, while through the basal membrane it induces activation of the canonical NF-kappa B pathway [ 20 ].
The differential spatial distribution of TLR in the epithelial cells reinforces the role of PRR signaling in innate immunity and may constitute a critical regulatory mechanism to distinguish commensal microbiota from pathogens.
The NLRs have been shown to play a key role in the defense against intracellular microbes, being capable of recognizing a broad range of exogenous bacterial components and toxins, as well as certain endogenous damage-associated molecular patterns DAMPs [ 21 ].
The NLR family comprises more than twenty cytosolic receptors in mammals, divided in different groups based on the N-terminal activation domains involved in signal transduction [ 14 ]. All these domains have been implicated in the triggering of alternative signaling pathways, including caspase and NF-kappa B activation, leading to the expression of inflammatory mediators and defensins, and the regulation of apoptotic signals [ 22 ].
Among the NLRs that recognize microbial molecules derived from peptidoglycan metabolism, only the NOD1 and NOD2 functions have been well characterized in the gastrointestinal tract.
In regard to tissue distribution, NOD1 receptors are constitutively expressed in a wide range of cells of both the hematopoietic and nonhematopoietic lineage, including intestinal epithelial cells [ 26 — 28 ].
Notably, in the epithelial compartment, NOD2 appears to be restricted to Paneth cells in the small bowel [ 29 ]. Because TLR signaling is downregulated within the intestine, in order to avoid continuous inflammation induced by the commensal microbiota, it is reasonable to suppose that NOD1 and NOD2 would then play a critical role in the host defense. Of note, both NOD1 and NOD2 may perform highly specialized and essential antimicrobial functions, such as regulation of antimicrobial peptides, therefore being critically important at mucosal surfaces [ 31 , 32 ].
In contrast to NOD1 and NOD2 stimulation, which are involved primarily in activation of inflammatory pathways, signaling through other NLR proteins results in activation of caspases. Oligomerization of these subunits through multiple complex molecular interactions results in the activation of caspase-1, which in turn catalyzes the cleavage of inactive IL-1 beta precursor, accumulated in the cytosol, determining the maturation of the inflammatory cytokines IL-1 beta and IL [ 33 , 35 , 36 ].
Specific inflammasome subtypes have been described, according to their respective NLR, each recognizing distinct MAMPs or other danger signals [ 37 ]. The pathogenesis of IBD has been regarded as multifactorial in origin, encompassing genetic susceptibility, epithelial barrier dysfunction, and an abnormal immune response to luminal contents, however, with an increasingly recognized role for innate immunity defects in the last ten years [ 7 , 43 ].
Most data on the role of TLR in the intestinal epithelium have derived from studies with experimental models and cell lines. In respect of the role of TLR in the human intestinal epithelium, investigations have yielded considerable heterogeneous results. In primary human epithelial cells, obtained from intestinal samples, the expression of TLR-2 and TLR-4 has been quite variable, being described at the crypts [ 44 , 45 ], in low levels [ 46 ] or even completely absent [ 47 ].
In regard to TLR5, it is noticeable that it is not widely expressed outside the gastrointestinal tract [ 49 ]. However, interestingly, its ligand flagellin is reported as a dominant epitope in sera from IBD patients [ 50 , 51 ], whereas it appears to trigger a cytoprotective effect in the gastrointestinal tract [ 52 , 53 ]. In experimental animals, TLR5 deficient mice have been demonstrated to develop spontaneous colitis [ 54 ], supporting the suggested protective role of TLR5 in humans.
Taken together, the findings regarding TLR expression and function in IBD, so far, suggest that colonic crypt epithelial cells may have a greater capacity to respond to stimuli derived from the intestinal microbiota. However, these studies fail to explain most of IBD associated heritability and have been directed to limited populations [ 57 ], while IBD is spreading all over the world [ 58 ]. In regard to NLRs, they are known to display a broad expression throughout the body, and the altered expression of these molecules in the intestinal tissues has been shown to be associated with the pathogenesis of intestinal inflammation, in both humans and experimental models [ 59 ].
For more than a decade, a defective NOD2 gene also termed caspase recruitment domain family, member 15, CARD15 has been known to constitute the most common genetic defect associated with CD [ 60 , 61 ]. Although it is well established that NOD2 activation elicits acute signaling effects, other diverse cellular modifications also appear to be relevant to the immune response and the intestinal homeostasis [ 63 ].
The NOD2-RIP2 complex then initiates a signaling cascade with potentially multiple outcomes, such as the activation of the IkB kinase IKK complex and MAPKs activation, with the consequent expression of cytokines, chemokines, and antimicrobial peptides [ 65 ], autophagy and resistance to intracellular microorganisms [ 66 ], and the modulation of antigen expression through the major histocompatibility complex [ 67 ] Figure 2.
Currently, it remains to be elucidated how the loss-of-function polymorphisms on NOD2 signaling determines the risk for CD development. Nevertheless, it has been proposed that decreased NOD2 function results in a defective interaction between the mucosal immune system and the intestinal microbiota, with an abnormal response to pathogens, potential bacterial invasion, and persistent intestinal inflammation [ 63 ].
It is intriguing to notice, however, that downstream NOD2 signaling dysfunction can be detected, even in the majority of CD patients who do not display NOD2 polymorphisms.
This evidence suggests a relatively limited participation of NOD2 in CD, but it also indicates an ambiguous role of the receptor in the pathogenesis of chronic intestinal inflammation. As NOD2 signaling emerges as a key regulator of NF-kappa B activation and the consequent induction of proinflammatory cytokines, it also has a critical role in mucosal protection.
On the other hand, the expressions of NOD2 per se, together with the proinflammatory cytokines, increase substantially also as a result of inflammatory stimuli [ 68 ]. In fact, this complex and bidirectional function of NOD2 appears to be dependent on the stage of the inflammatory disease [ 69 ]. For example, it has been shown that children with CD display an overexpression and hyperactivity of NOD2 and RIP2, its obligate caspase-recruitment domain-containing kinase, in biopsy samples from the intestinal inflamed mucosa [ 70 ].
However, while NOD2-deficient mice do not develop intestinal inflammation spontaneously, they were shown to be more susceptible to microbial infection, particularly through the oral route [ 31 ]. Furthermore, in another IBD experimental model, ILdeficient mice did not develop colitis when NOD2 gene deletion was simultaneously introduced into these mice [ 71 ]. Hence, this result is consistent with the notion that NOD2 mutations might be implicated in CD pathogenesis, by leading to an excessive Th1-type of immune response [ 72 ].
Currently, it appears that the understanding of NOD2 functions is still incomplete, especially after the identification of susceptibility variants related to autophagy in CD. In fact, NOD2 and autophagy genes share various similar functions. Because autophagy has been implicated in cellular homeostasis and also in the immune response, through the removal of cell debris and bacterial elements [ 74 ], it is reasonable to suppose its potential in the pathogenesis of CD.
Interestingly, interaction between NOD2 and autophagy genes has been demonstrated recently. Upon exposure to ligands mostly present in Gram-negative bacteria, NOD1 undergoes a conformational modification that initiates a signaling cascade that culminates with the activation of NF-kappa B and MAPK pathways and inflammatory responses [ 78 ] Figure 2.
Although NOD1 receptor has been considered as a candidate factor for susceptibility to IBD, data on NOD1 gene polymorphisms from different studies have provided conflicting results [ 79 , 80 ].
Among the four types of inflammasomes described so far, the NLRP3 has been the more consistently associated with CD susceptibility [ 81 , 82 ].
In a different population with different genetic background, susceptibility to CD was also related to a NLRP3 polymorphism. In contrast to the previous study, investigators reported a gain-of-function polymorphism, proposing a different mechanism, which consists of the induction of caspase-1 activity and the resultant overproduction of IL-1 beta [ 82 ]. In consonance with the importance of defects of NLRP3 for the development of intestinal inflammation, studies analyzing its downstream molecules such as IL confirmed the association with the increased susceptibility to CD [ 84 ].
In addition, in sites of active intestinal inflammation in CD, IL [ 85 ] and IL-1 beta [ 86 ] were shown to be overexpressed. For example, pannexin-1, a transmembrane hemichannel associated with the purinergic receptor P2X7, has been proposed to function upstream of NLRP3, as it has been shown to mediate the passage of microbial molecules into the cytosol, triggering NLRP3-inflammasome activation [ 87 ].
Moreover, as demonstrated by our group, the site-specific expression and modulation within the gut and gut-associated lymphoid tissues [ 88 ] and the upregulation of the P2X7 receptor in an inflammatory microenvironment [ 89 ], together with the induction of epithelial cell apoptosis and autophagy by its ligand ATP [ 90 ], point to purinergic signaling as a key regulator of the innate immune response and of the activation of the NLRP3-inflammasome.
The NLRC4-inflammasome is predominantly expressed in myeloid cells and is composed of an N-terminal CARD domain, which is thought to interact directly with caspase-1 [ 91 ], mediating cytokine production and the induction of cell death [ 92 ]. Activation of NLRC4 may have an important role in the defense against diverse Gram-negative bacteria, such as Salmonella typhimurium , Shigella flexneri , Legionella pneumophila, and Pseudomonas aeruginosa [ 93 , 94 ], but also Candida albicans [ 95 ] and Burkholderia pseudomallei , a flagellated bacterium responsible for a tropical pneumonia [ 96 ].
In experimental and in in vitro experiments, macrophages were shown to sense the cytosolic bacterial flagellin proteins with resultant caspase-1 activation in a TLR5-independent fashion [ 97 , 98 ].
The NLRP6-inflammasome has also been associated with intestinal inflammation, basically in experimental studies. For example, in NLRP6 deficient mice, the exacerbation of chemically induced colitis has been linked to the inability of repairing the injured epithelium [ 99 ]. Moreover, cohousing experiments demonstrated that the colitogenic microbiota could be transferable to wild-type mice [ ]. Importantly, the NLRP6-inflammasome was also suggested to be involved in colon tumorigenesis.
In this respect, NLRP6-deficient mice were shown to develop more tumors, following chemical induction with azoxymethane-dextran sodium sulfate [ ]. The NLRP12 was also shown to play a role in preventing chemically induced colitis and colon tumor associated with inflammation [ ], by negatively regulating of noncanonical NF-kappa B signaling [ ]. However, in contrast to NLRP6, the NLRP12 effects do not appear to be associated with the regulation of the intestinal microbiota, as shown by the inability of NLRP12 deficient mice to transmit colitogenic bacteria to wild-type mice after cohousing [ ].
Taken together, the results of these studies point to the relevance of the inflammasome, regarding the innate immunity and the consequent homeostatic intestinal balance. Hence, the integration of internal and external stimuli, including stressful signals and microbial components, highlights the importance of the inflammasome, which appears to constitute a mechanistic background for intestinal inflammation and the development of inflammation-associated tumorigenesis.
Recent investigations have provided evidence for a conceptual change in respect of the innate immune system.
At first, regarded as nonspecific, the idea of innate immunity has evolved to constitute an integrative system, connecting adaptive and innate immune responses. Therefore, currently, in addition to early sensing of pathogens and delivering and immediate response, the innate immune system is implicated in the regulation and shaping of the adaptive immune response.
The hypothesis of a defective innate immunity as the primary mechanism involved with the development of IBD has been supported for more than a decade. After the first evidence indicating the genetic association of CD with NOD2 polymorphisms, a multitude of studies have been directed towards innate immunity mechanisms in IBD pathogenesis.
New members of the NLRs and TLRs have been described and their functions analyzed under the light of intestinal inflammation.
The pathways regulated by NLRs and TLRs were shown to be mediated by microbial elements, and they appear to be responsible for bacterial clearance and the inflammatory response, in a time-dependent fashion. In fact, most receptors of the innate immunity present ambiguous functions, according to the dynamics of the inflammatory process.
NOD2 and inflammation: current insights
NOD1 and NOD2 belong to the family of intracellular Nod-like receptors NLRs that are involved in the maintenance of tissue homeostasis and host defense against bacteria and some viruses. When sensing such microbes, those NLRs act as hitherto scaffolding proteins for activating multiple downstream inflammatory signaling pathways to promote the production of cytokines and chemokines that are ultimately important for pathogen clearance. In recent years, substantial advances have been made on our understanding of a contextual series of intracellular processes that regulate such group of innate immune molecules, including phosphorylation and ubiquitination. Specifically, we will herein discuss those recently described posttranslational modifications of either NOD1 or NOD2 that fundamentally contribute to the robustness of protective responses within specific tissues through either internal domain association or external interactions with various proteins. From a public health perspective, it is then anticipated that a better understanding how genetic mutations and deregulation of these activating and repressing mechanisms might break down in diseases would open up new therapeutic avenues for humanity.
The nucleotide-binding oligomerization domain NOD protein, NOD2, belonging to the intracellular NOD-like receptor family, detects conserved motifs in bacterial peptidoglycan and promotes their clearance through activation of a proinflammatory transcriptional program and other innate immune pathways, including autophagy and endoplasmic reticulum stress. An inactive form due to mutations or a constitutive high expression of NOD2 is associated with several inflammatory diseases, suggesting that balanced NOD2 signaling is critical for the maintenance of immune homeostasis. In this review, we discuss recent developments about the pathway and mechanisms of regulation of NOD2 and illustrate the principal functions of the gene, with particular emphasis on its central role in maintaining the equilibrium between intestinal microbiota and host immune responses to control inflammation. Furthermore, we survey recent studies illustrating the role of NOD2 in several inflammatory diseases, in particular, inflammatory bowel disease, of which it is the main susceptibility gene. The human body is constantly in contact with a myriad of microorganisms, either pathogens or commensals. Innate immune system, which provides a first line of defense against many common microbes, is essential for an appropriate tissue homoeostasis as well as for common bacterial infections, and its dysfunction leads to infectious, inflammatory and autoimmune diseases.
NOD-Like Receptors: Master Regulators of Inflammation and Cancer
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The Role of Innate Immunity Receptors in the Pathogenesis of Inflammatory Bowel Disease
Innate immunity constitutes the first line of defense, fundamental for the recognition and the initiation of an inflammatory response against microorganisms. The innate immune response relies on the sensing of microbial-associated molecular patterns through specialized structures such as toll-like receptors TLRs and the nucleotide oligomerization domain- NOD- like receptors NLRs. In the gut, these tasks are performed by the epithelial barrier and the presence of adaptive and innate immune mechanisms. TLRs and NLRs are distributed throughout the gastrointestinal mucosa, being more expressed in the epithelium, and in lamina propria immune and nonimmune cells. These innate immunity receptors exhibit complementary biological functions, with evidence for pathways overlapping.
Cytosolic NOD-like receptors NLRs have been associated with human diseases including infections, cancer, and autoimmune and inflammatory disorders. These innate immune pattern recognition molecules are essential for controlling inflammatory mechanisms through induction of cytokines, chemokines, and anti-microbial genes. Moreover, NLRs and their downstream signaling components engage in an intricate crosstalk with cell death and autophagy pathways, both critical processes for cancer development. Recently, increasing evidence has extended the concept that chronic inflammation caused by abberant NLR signaling is a powerful driver of carcinogenesis, where it abets genetic mutations, tumor growth, and progression. In this review, we explore the rapidly expanding area of research regarding the expression and functions of NLRs in different types of cancers. Furthermore, we particularly focus on how maintaining tissue homeostasis and regulating tissue repair may provide a logical platform for understanding the liaisons between the NLR-driven inflammatory responses and cancer.
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