File Name: nod proteins regulators of inflammation in health and disease .zip
- The Role of Innate Immunity Receptors in the Pathogenesis of Inflammatory Bowel Disease
- The Ubiquitin Code of NODs Signaling Pathways in Health and Disease
- NOD proteins: regulators of inflammation in health and disease
- NOD-Like Receptors: Master Regulators of Inflammation and Cancer
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.
The Role of Innate Immunity Receptors in the Pathogenesis of Inflammatory Bowel Disease
Correa; NOD-like receptors: major players and targets in the interface between innate immunity and cancer. Innate immunity comprises several inflammation-related modulatory pathways which receive signals from an array of membrane-bound and cytoplasmic pattern recognition receptors PRRs. Disruption of those signals may lead to a number of pro-inflammatory conditions, eventually promoting the onset of human malignancies. In this review, we describe the structures and functions of the most well-defined NLR proteins and highlight their association and biological impact on a diverse number of cancers.
The innate immune system is our first line of defense against infections from an enormous diversity of microbes and viruses. The human innate immunity relies on a wide range of receptors and complex downstream networks which respond against infectious pathogens.
Disruption in the balance of these signals may lead to chronic inflammatory states and directly affect cellular processes, such as cell cycle progression and apoptosis, creating a background context for the rise of maladies, such as cancer [ 1 , 2 ].
In humans, innate immune receptors are classified into several families [ 3 ]. While TLRs act as surface receptors found in cell and organelle endosome membranes, the NLRs are cytosolic receptors involved in the detection of intracellular pathogens and endogenous byproducts of tissue injury [ 7 ].
Typically, the PAMPs recognized by NLRs are bacterial cell-wall derivates [ 10 ], microbial toxins [ 11 ], viruses [ 12 ] or even whole pathogenic microbial organisms [ 13 ]. A number of NLR homologs have been described in both vertebrate and invertebrate species [ 22 ].
In humans, the NLR protein family comprises 22 members [ 23—25 ]. All NLR proteins share a typical architecture, including: i a centrally located nucleotide-binding NACHT domain, which mediates self-oligomerization and is essential for ATP-dependent NLR activation; ii an N-terminal effector domain, which interacts with adaptor molecules and downstream effectors to mediate signal transduction; and iii a C-terminal region, comprising variable numbers of LRR domains, involved in the recognition of molecular patterns Figure 1 [ 4 ].
Specifically, human NLRs are divided into four subfamilies, according to the nature of their N-terminal regions. Green open circles represent LRR Leucine-rich repeat. GTP binding facilitates the protein transport into the nucleus, where it acts as a positive regulator of class II major histocompatibility complex gene transcription Figure 2 [ 26 ]. In this case, transcriptional activation is not achieved through DNA binding, but via an intrinsic acetyltransferase AT activity [ 27 , 28 ].
NAIP is a mediator of neuronal survival in several pathological conditions, preventing apoptosis induced by a variety of signals [ 31 ]. Lightning arrows indicate specific signaling nodes or receptor s for which gene mutations or alterations in expression levels have been reported in association with major types of cancer adjacent boxes.
NOD1 and NOD2 recognize intracellular bacterial components, which enter the cell either via direct bacterial invasion or by other cellular uptake mechanisms [ 34 , 35 ].
Therefore, NOD2 acts as a broader sensor of bacterial infection, while NOD1 recognizes a more specific subset of bacterial strains. The NLRP subfamily of receptors consist of 14 members, characterized by the presence of an N-terminal pyrin PYD effector domain [ 39 ] which possesses a conserved sequence motif found in more than 20 human proteins, with functions in apoptotic and inflammatory signaling [ 8 , 39 ].
Studies have shown that NLRP genes play important roles in both the innate immune system and mammalian reproduction [ 8 , 40 ], suggesting that NLRPs might play a role in oogenesis and early preimplantation embryogenesis [ 8 , 40 ]. NLR activation is translated through distinct subpathways to achieve pro- or anti-inflammatory responses Figure 2. The downstream signals involved are modulated by the type of ligands bound to the NLR and may also depend on the cellular context.
For instance, NOD1 and NOD2 receptors bind to the membrane of early endosomes in the cytoplasm, specifically interacting with the actin cytoskeleton in order to maintain an inactive state [ 41 , 42 ]. PGNs that are transported through the membrane [ 43—48 ] are promptly recognized by these NOD receptors. These receptors can detect intracellular bacteria which cross the plasma membrane and then recruit the autophagic essential adapter protein ATG16L1 to the bacterial entry site, promoting highly specific lysosome-mediated degradation of the invading microbe by the autophagic machinery [ 21 , 57—59 ].
The inflammasome is a multiprotein intracellular complex, which is frequently formed in response to several pathophysiological stimuli [ 67 ]. Despite its cytosolic localization, inflammasome structures are capable of launching an effective immune response against bacteria, fungi and viruses [ 68 ].
In resting cells, caspase-1 is present in a catalytically inactive pro-form zymogen called pro-caspase-1 [ 72 ]. Caspases have long been established as executioners of the apoptotic response, also contributing to inflammasome activation [ 69 ]. The secretion of these cytokines may lead to pyroptosis, a term used to describe the inherently inflammatory process of CASP1-dependent programmed cell death [ 75 , 76 ]. NLRP1 has been described to bind directly to its ligand MDP in vitro , with this interaction apparently being sufficient to activate the inflammasome assembly [ 70 ].
Genetic variation in the human Nlrp1 gene has been linked to increased susceptibility to certain autoimmune diseases [ 81 ], systemic lupus [ 82 ] and cancer [ ]. Studies have also demonstrated a genetic association of polymorphisms in Nlrp1 gene in driving the tumorigenic process, which leads to an increase in the production of downstream mediators i.
NLRP1 -like genes are found in most, if not all, mammalian species for which a genome has been sequenced, including primates, rodents, ungulates and marsupials [ 84 ].
The murine NLRP1b is involved in the mechanism by which Bacillus anthracis infection activates caspase-1 [ 86 ]. NLRP1b also serves as an inflammasome sensor for Toxoplasma gondii , leading to an inflammasome response in rats and, consequently, limiting parasite load and dissemination [ 87 ]. Still, more studies are warranted to describe the precise mechanism of T.
The NLRP3 inflammasome is activated by a number of factors, which include: Gram-positive bacteria, viruses such as influenza , fungi and protozoa, toxins such as hemolysin , ATP, potassium efflux, and reactive oxygen species ROS [ 70 , 89—91 ].
Some studies link various adaptor proteins, such as guanylate-binding protein GBP [ 93 , 94 ], thioredoxin TRX -interacting protein TXNIP [ 89 ], amongst others shown to be critical for mammalian host defense.
Altogether, the NLRP3 inflammasome integrates multiple signals to protect the host against different forms of cellular stress [ 95 ]. Nevertheless, the mechanisms governing the formation and activation of the NLRP3 inflammasomes, in certain cellular contexts, still deserve further investigation.
NLRC4 is also an important sensor for the activation of caspase-1, particularly in macrophages infected with Salmonella strains [ 96 ]. This sensor is typically activated by a more streamlined set of ligands, which includes bacterial flagellin and components of the bacterial T3SS Type 3 secretion system proteins [ 97 ]. NLRC4 appears to detect these ligands by recognizing pathogen derivatives, which are secreted into the host cell cytosol by certain bacterial strains [ 84 ].
Inflammation has a dual role in cancer onset and progression. Pro-inflammatory condition has been described as a crucial state for cancer onset, progression, angiogenesis, and metastasis [ 98— ], being related to chronic low-grade activation of the immune system as a result of the production of several downstream pro-inflammatory factors [ ]. On the other hand, immunosurveillance can prevent cancer onset and limit tumor growth [ , ].
Biomolecules that are produced by tumor-infiltrating immune cells, such as cytokines, proteases, reactive oxygen and nitrogen species, can influence the microenvironment and act as intermediates in these pathological processes [ — ]. The microenvironmental changes caused by the immune infiltrate include alterations i in the tumoral extracellular matrix and ii in the interaction between the different cell populations of the tissue, resulting in epigenetic modifications, epithelial—mesenchymal transition EMT , oncogenes expression promotion and silencing of tumor suppressors [ — ].
Here, we briefly discuss the inflammation mechanisms driven by distinct NLRs and their association with a substantial number of relevant malignancies. A snapshot of major cancer types associated with each NLR is shown in Figure 2 , while a list of reports linking NLRs to a number of cancers is presented in Tables 1 and 2. The incidence of PMBCL is higher in young adults and adolescents, with a metastatic potential to invade surrounding tissues [ ]. In addition, NAIP expression in these malignant tissues is correlated with tumor size, but not with relapse-free survival [ ].
More mechanistic studies are still warranted to confirm whether NAIP is relevant to breast cancer biology. Not only NAIP expression in colon cancer samples was found to be lower than in normal mucosa [ ] but also, based on a model of colitis-associated cancer, mice lacking NAIP paralogs Naip display a higher susceptibility for CRC in an inflammation-independent mechanism [ ].
Furthermore, these knockout mice displayed increased STAT3 expression and failed to activate p53 upon carcinogen exposure [ ]. This suggests that NAIPs may act as tumor suppressors in vivo by inducing apoptosis in carcinogen-affected cells. Prostate cancer PCa is the most common cancer in men [ , ]. Advanced PCa, submitted to androgen deprivation therapy, displays increased NAIP expression, which may possibly contribute to docetaxel resistance [ ].
Obesity has been associated with a poor prognosis of breast cancer patients, since adipose cells stimulate angiogenesis and synthesize estrogen, a primary female hormone that impacts tumor growth and metastatic potential [ ].
For instance, in an orthotopic model, obese mice displayed higher tumor-infiltrating myeloid cells content and higher tumor-angiogenesis [ ]. Cross-talk between tumor tissue and immune infiltrates also leads to vascular endothelial growth factor A VEGFA -mediated angiogenesis in an NLRC4-dependent manner, therefore driving disease progression [ ]. In ER-positive MCF-7 cells, NOD1 deficiency correlates with tumor growth, an increased sensitivity to estrogen-induced cell proliferation and impaired Nod1-dependent apoptosis.
Correspondingly, in the same cells, NOD1 overexpression inhibited ER-dependent tumor growth and reduced estrogen proliferative response in vitro [ ]. Apparently, Nod1-dependent apoptosis is mediated by a caspase 8-cascade in an RIP2-dependent manner [ ].
More recently, it has been described that overexpression of either NOD1 or NOD2, in the triple negative HsT cells, is able to reduce cell proliferation but increase clonogenic potential in vitro [ ].
Based on this staging, CRC is classified from stage I to IV in which i stage I tumors have breached beyond the inner lining of the colon, ii stage II tumors invaded the muscular wall of the colon, iii stage III tumors have reached the lymph nodes and iv stage IV tumors have metastasized to other organs besides the lymph nodes [ ].
This correlation might be explained by recent reports describing the link between NLRC3 and the concomitant suppression of cellular proliferation and induction of cell death through the inhibition of the PI3K-mTOR signaling pathway in different node points [ ]. Likewise, caspasedeficient mice submitted to the same treatments show increased epithelial cell proliferation in early stages of oncogenesis, and apoptosis evasion in additional stages in an NLRC4-dependent manner [ ].
NLRC deficiencies are also correlated to immunosurveillance escape-mediated tumor progression [ ]. It is interesting to note a correlation between reduced NLCR5 expression and higher CRC risk, especially in mismatch repair-deficient tumors [ — ]. Furthermore, NOD2 deficient mice are seemingly more prone to colitis and colitis-related cancer due to induced instability in the composition of gut microbiome [ ].
This increased susceptibility to inflammation could be prevented by i microbiota transplantation, ii antibiotics or iii anti-IL-6 neutralizing antibody treatment [ ]. Helicobacter pylori infection is a strong risk factor for gastric cancer GC [ ]. In this context, expression of the epithelial-specific transcription factor CDX2 is known to contribute to intestinal metaplasia an event that precedes GC and to be induced by H.
This is somewhat contradictory to the findings in which, upon H. Here, we describe some of the main findings linking NLRPs to different human malignancies. Cervical cancer is the second most common cancer type in women [ ].
It has been found that persistent Human Papillomavirus HPV infection, associated with chronic inflammation, may lead to cancer onset [ ]. Inflammation is highly associated with the onset of CRC. Interestingly, high-fat diet has also been associated with NLRP3 activation and increased tumor susceptibility [ , ]. High-fat diet leads to an increase in deoxycholic acid levels in the intestine, which, in turn, disrupts the cell monolayer integrity by decreasing the expression of the tight junction protein ZO-1 [ ].
This disruption in the mucosal barrier leads to an increased tissue inflammation, mediated by NLRP3, and further polarization of M2 macrophages [ ]. Likewise, azoxymethane-treated mice submitted to a cholesterol-rich diet show increased tissue inflammation and higher susceptibility to tumor development [ ]. This cascade of events can be partially reverted by NLRP3 depletion [ ]. NLRP3 expression has also been found in macrophages infiltrated in CRC tissues, and the inhibition of NLRP3 pathway leads to decreased tumor cell migration, invasion and metastatic potential [ ].
These data are supported by the evidence that treatment with a small-molecule AMPK activator GL-V9 , which acts as an anti-inflammatory molecule on macrophages, triggers autophagy and NLRP3 degradation, providing a protective effect against colitis and CRC [ ]. Although NLRP3 expression in tissue-infiltrated macrophages has been associated with higher susceptibility to CRC and its aggressiveness, its role in tumor cells is, at a first glance, controversial.
In addition, NLRP3 knockout mice display augmented liver metastasis [ ], which is also due to the impairment of IL signaling. This suppression affects Fas ligand FasL expression in natural killer cells NK cells , thus compromising their ability to kill FasL-sensitive tumor cells [ ].
One example is its role as an effector of TRAIL tumor necrosis factor related apoptosis-inducing ligand , an apoptosis-inducing protein whose use for cancer treatment has been currently evaluated [ — ]. In this context, mice submitted to the azoxymethane-DSS CRC model and treated with recombinant TRAIL displayed inhibition of macrophage recruitment to the damaged mucosa, therefore diminishing acute inflammation [ ].
These studies emphasize the multifunctional role of NLRP3, as well as the importance of the cross-talk between the different resident tissue cells and the CRC outcome. For instance, NLRP6, typically produced by the stem-cell niche, acts on the self-renewal of the colon epithelium upon injury and, therefore, it is important for the integrity and homeostasis of the epithelial barrier [ ]. Indeed, NLRP6 deficient mice show impaired regeneration of the mucosa upon injury, and they are susceptible to colitis-associated tumor growth [ ].
Nevertheless, due to the dual role of inflammation in cancer development, further studies are still warranted to better explore the clinical potential of some inflammasome-related proteins.
The Ubiquitin Code of NODs Signaling Pathways in Health and Disease
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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.
Request PDF | On Feb 1, , D.J. Philpott and others published Erratum: NOD proteins: Regulators of inflammation in health and disease (Nature Reviews.
NOD proteins: regulators of inflammation 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.
NOD2 nucleotide-binding and oligomerization domain 2 was initially reported as a susceptibility gene for Crohn's disease, with several studies focused on elucidating its molecular mechanism in the progression of Crohn's disease. Various mutations in NOD2 have been reported, with NOD2 loss of function being associated with the development of Crohn's disease and other autoimmune diseases.
NOD-Like Receptors: Master Regulators of Inflammation and Cancer
Atherosclerosis is crucially fueled by inflammatory pathways including pattern recognition receptor PRR -related signaling of the innate immune system. Currently, the impact of the cytoplasmic PRRs nucleotide-binding oligomerization domain-containing protein NOD 1 and 2 is incompletely characterized. Deficiency of Nod1 and Nod2 led to reduced plaque lipid deposition and inflammatory cell infiltration in atherosclerotic plaques. This might be explained by diminished plasma lipid levels and foam cell formation due to altered expression of key regulators of the hepatic cholesterol pathway as well as differential intestinal cholesterol metabolism and microbiota composition.
Correa; NOD-like receptors: major players and targets in the interface between innate immunity and cancer. Innate immunity comprises several inflammation-related modulatory pathways which receive signals from an array of membrane-bound and cytoplasmic pattern recognition receptors PRRs. Disruption of those signals may lead to a number of pro-inflammatory conditions, eventually promoting the onset of human malignancies. In this review, we describe the structures and functions of the most well-defined NLR proteins and highlight their association and biological impact on a diverse number of cancers. The innate immune system is our first line of defense against infections from an enormous diversity of microbes and viruses. The human innate immunity relies on a wide range of receptors and complex downstream networks which respond against infectious pathogens.
Mediators of Inflammation
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 innate immune system contributes to the first defensive actions against trauma and a plethora of microbes. It relies on a wide range of germline-encoded pattern recognition receptors PRRs that detect signals from either pathogens or injured host cells 1 , 2.
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Вскоре путь ей преградила кабина голосового сканирования, табличка на которой гласила: АГЕНТСТВО НАЦИОНАЛЬНОЙ БЕЗОПАСНОСТИ (АНБ) ОТДЕЛЕНИЕ КРИПТОГРАФИИ ТОЛЬКО ДЛЯ СОТРУДНИКОВ С ДОПУСКОМ Вооруженный охранник поднял голову: - Добрый день, мисс Флетчер. - Привет, Джон. - Не ожидал, что вы придете .
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Очевидно, она перевела свое имя на единственный язык, равно доступный ей и ее клиенту, - английский. Возбужденный, Беккер ускорил шаги в поисках телефона. По другой стороне улицы, оставаясь невидимым, шел человек в очках в тонкой металлической оправе. ГЛАВА 27 Тени в зале шифровалки начали удлиняться и терять четкость.
Люди на соседних койках приподнялись и внимательно наблюдали за происходящим. В дальнем конце палаты появилась медсестра и быстро направилась к. - Хоть что-нибудь, - настаивал Беккер.