File Name: nod proteins regulators of inflammation in health and disease .zip
- The Ubiquitin Code of NODs Signaling Pathways in Health and Disease
- The Role of Innate Immunity Receptors in the Pathogenesis of Inflammatory Bowel Disease
- NOD proteins: regulators of inflammation in health and disease
- NOD2 and inflammation: current insights
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.
The Ubiquitin Code of NODs Signaling Pathways in Health and Disease
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.
Finally, we outline novel therapeutic approaches that target NLR signaling and speculate how these could be developed as potential pharmaceutical alternatives for cancer treatment. Over the past two decades, immunologists have begun to appreciate the complexity of the innate immune system, its importance as the first wave of defensive action against perceived harmful microbes or foreign particles and its functions in triggering antigen-specific responses by engaging the adaptive immune system.
Innate immune responses are orchestrated by germline-encoded pattern recognition receptors PRRs 1. PRRs recognize conserved pathogen-derived and damaged self-derived molecular components, commonly referred to as pathogen associated molecular patterns PAMPs and danger associated molecular patterns DAMPs , respectively 2 , 3.
PRR superfamilies are broadly classified based upon structural homology and the requirement of different adaptor proteins that ensure their function and downstream signal transduction 4. Evidence in the field points to a paramount importance of NLRs in human diseases with increasing interest in translating this knowledge toward clinical benefits. Due to the active role of NLRs in regulating pro-inflammatory signals and recruiting the adaptive arm of the immune system, dysregulation of microbial sensing has been reported to influence disease outcomes and tumorigenesis In this review, we will describe the crucial roles of NLRs in cancer development and progression, and discuss the possibility of NLRs as targets for tumor therapy.
Observations by Rudolf Virchow in the nineteenth century indicated a link between inflammation and cancer, and suggested that immune and inflammatory cells are frequently present within tumors. Indeed, chronic inflammation plays critical roles in various stages of cancer development and progression 11 — Many cancer risk factors are associated with a source of inflammation or act through inflammatory mechanisms such as those evoked by bacterial and viral infections 14 , tobacco smoke 15 , obesity 16 , 17 , and aging or cell senescence 18 , While some cancers arise from chronic inflammation or after immune deregulation and autoimmunity, solid malignancies elicit intrinsic immune mechanisms that guide the construction of a tumorigenic microenvironment 12 , 13 , Although the exact mechanism of how inflammation leads to neoplastic transformation is not fully known, it is suggested that inflammatory immune cells like macrophages and T cells are the main orchestrators of inflammation-mediated tumor progression.
These cells secrete cytokines and chemokines that cause DNA damage, generate mutagenic reactive oxygen species ROS , and supply cancer cells with growth factors In addition, inflammatory mechanisms were shown to promote genetic instability by impairing DNA repair mechanisms, altering cell cycle checkpoints, and often facilitating epigenetic silencing of anti-tumor genes, thus contributing to the high degree of genetic heterogeneity in tumors Oncogenic mutations prompted by an inflammatory microenvironment frequently cause neoplastic transformation by promoting excessive proliferation and resistance to cell death Indeed, impaired expression and activity of proteins that control cell survival, such as the inhibitor of apoptosis proteins IAPs and the BCL2 family of proteins, is a common occurrence in many cancers 23 , Typically known to exert strong anti-apoptotic functions, IAPs neutralize pro-apoptotic second mitochondrial activator of caspases SMAC and inhibit activation of apoptotic caspases, thereby promoting cell survival during both physiological stresses and pathogenic stimulations 25 — Owing to their strong pro-survival potency, enhanced expression of IAPs has been correlated with several human cancers Unlike IAPs, the BCL2 family of proteins consists of both pro- and anti-apoptotic proteins that control critical checkpoints of intrinsic apoptosis by regulating mitochondrial integrity and release of cytochrome c into the cytosol Deregulation of the functions of BCL2 proteins, i.
It was described that the transcription factor p53 senses physiological stresses and is critical for restraining tumor growth. Indeed, loss of p53 expression or function in both humans and mice has been proven to promote sporadic tumorigenesis 34 , Induction of target genes that inhibit cancer progression is generally considered to be the canonical mechanism of pmediated tumor-suppression. These target genes directly modulate cellular programs involving induction of apoptosis, cell cycle arrest, and promotion of cellular senescence and DNA repair Recently, non-canonical functions of p53 have come to light, like the regulation of cellular metabolism, cell-to-cell communication, autophagy, tumor invasion, and metastasis, making p53 an attractive pharmaceutical target for treating cancers [reviewed in Ref.
Early detection of rogue tumor cells by the innate immune cells and their rapid removal is a key host defense strategy for evading tumorigenesis. In particular, natural killer NK cells are primary sentinels that guarantee such immune surveillance by differentiating normal cells from stressed or tumor cells via the expression of specific NK receptors Indeed, increased presence of NK cells at tumor sites has been reported to improve remission, whereas decreased NK cell anti-tumor activity has been correlated with a greater likelihood for developing cancer However, recent data from Soares et al.
Additionally, Rebsamen et al. Overall, the precise role of NLRX1 remains controversial and further research is required to validate its pro or anti-inflammatory properties. Schematic representation of individual NLR domains. Domain architecture of human NLRs is depicted here. Dysregulated apoptosis and autophagy pathways, as well as excessive chronic inflammation are major drivers of carcinogenesis.
NLRs are innate immune sensors that actively communicate with a myriad of cell death regulators. Hence, these PRRs are well-positioned to influence tumor development and progression particularly at sites with high host-microbiome interactions like the gut. One of the mysteries of the innate immune system is how do NLRs sense molecular patterns from both commensal and pathogenic microorganisms and manage to tolerate one while help eradicate the other 5 , This disparity in NLR functions is particularly useful in the intestinal epithelia where host cells are in constant contact with millions of microbes.
Consequently, it came as little surprise when common variants in the NLR genes were correlated with the incidence of CD and susceptibility to cancers 50 , 62 — Due to these correlations, most of the studies have been focused on understanding the mechanisms by which NODs and inflammasome NLRs regulate intestinal inflammation and tumorigenesis.
NOD1 is expressed in both hematopoietic and non-hematopoietic cells and responds to intracellular gamma- d -glutamyl-meso-diaminopimelic acid iE-DAP mostly present on Gram-negative bacteria and only on some select Gram-positive bacteria, like Listeria and Bacillus species 65 — Unlike NOD1, NOD2 expression is largely restricted to hematopoietic cells and certain specialized epithelial cells such as the small intestinal Paneth cells Besides providing immunity against intracellular bacteria, NODs were revealed to be critical for host defense against non-invasive Gram-negative bacteria like Helicobacter pylori , following delivery of its PGN into the host cells through the bacterial type IV secretion system Notably, NOD1 and NOD2 have been reported to localize to the plasma membrane at the sites of infection; however, the biological relevance of this translocation remains elusive 74 , Indeed, cells or mice lacking RIP2 do not respond to NOD agonists and fail to produce pro-inflammatory and anti-microbial molecules 78 — While this model still stands true, over the years new body of research has contributed a wealth of data regarding specific sequence of events that leads to RIP2 activation.
In contrast to the earlier studies 82 — 85 , recent in vitro data using pharmacological inhibitors as well as in vivo evidence using a knock-in mouse with kinase-dead RIP2 K47A have highlighted the key role of the kinase activity of RIP2 in NOD-mediated immune responses 86 , Stimulation of both arms culminates in the induction of anti-microbial peptides AMPs , cytokines, and chemokines.
The formation of the Nodosome promotes autophagy and conversely, a fully functional autophagy machinery helps in signal transduction through the Nodosome. Similarly, several studies have alluded to NODs as being regulators of caspase-mediated apoptosis 82 , , ; yet, no direct link has so far been reported. Notably, BID was phosphorylated upon activation with NOD agonists and these innate immune functions of BID were found to be independent of its pro-apoptotic processing by caspase-8 The discovery involving a classical pro-apoptotic protein, such as BID, in NOD—RIP2 signaling strengthens the concept that inflammatory and cell death pathways do not function as discrete mechanisms but share common adaptors.
Taken together, this information suggests that different NLRs can have opposing regulatory effects on autophagy and cell death, yet the molecular triggers that dictate these actions are not fully understood. Notably, such inactivation of NOD2 immunity has been indicated to enhance the risk of bacterial infections following chemotherapy in patients with acute myeloid leukemia In addition, NOD2 polymorphisms have been correlated with modifications in gastric mucosa and increased risk for H.
Apart from intestinal disorders, mutations in NOD2 have been linked with increased prevalence of early onset breast and lung cancers , However, how NOD2 contributes to the initiation and the progression of cancer remains ill defined. Although no mutations in the NOD1 gene have been so far associated with the incidence of intestinal inflammation or even colorectal cancer CRC , murine models clearly designate a central anti-tumorigenic function for NOD1 in the pathophysiology of disease.
This experimental CRC model is particularly applicable when the focus is on understanding colitis-driven tumor initiation and progression. While most investigations have been focused on the role of NOD1 in models of intestinal tumorigenesis, one report provided experimental evidence for the protective role of NOD1 in breast cancer This transmissible phenotype was significantly ameliorated upon treatment with broad-spectrum antibiotics or using the neutralizing IL-6 receptor antibody Altogether, these findings reinforce the idea that aberrant NOD signaling gives rise to dysbiosis that in an inflammatory setting ultimately causes mucosal injury and drives CRC.
So far, the translational value of this knowledge is limited but with the recent technological advances in the microbiome research it is predicted that modulation of dysbiosis could be used as a therapeutic strategy for patients with CD as well as CRC.
Contrary to the protective role for NODs in intestinal tumorigenesis, increased expression of both NOD1 and NOD2 has been reported in the head and neck squamous cell carcinoma biopsies as compared to the healthy nasal biopsies. These findings implicate NODs in enhancing head and neck cancers; however, thus far no corroborating experimental evidence has been reported To date, various inflammasome platforms have been described , but the NLRP3 inflammasome is the most commonly studied.
Classically, the inflammasome has been described to consist of an NLRP, the inflammatory protease caspase-1, and the apoptosis-associated speck like protein ASC Simplified mechanisms for the canonical NLRP3- inflammasome activation.
Clearance of distressed mitochondria by mitophagy serves to evade such inflammasome activation. Activation of the NLRP3-caspase-1 axis results in inflammation and pyroptotic cell death. The NLRP3-inflammasome formation requires a two-step process However, certain cells like the human blood monocytes and murine macrophages appear to activate the NLRP3 inflammasome in response to LPS stimulation alone , It is noteworthy that a transcriptionally silent mechanism for TLR4-mediated inflammasome priming has been lately discovered , The second activation step or signal 2 promotes the NLRs to undergo homotypic oligomerization and assemble the inflammasome.
While several models have been proposed to define the signals behind NLRP3 activation, the precise mechanisms remain hitherto unresolved. Various bacterial pathogens induce potassium efflux and activate the NLRP3 inflammasome via the action of secreted pore-forming toxins e. In addition, NLRP3 inflammasomes have been known to assemble in response to cytosolic bacterial and viral RNA both in vivo and in vitro , — Extracellular adenosine tri-phosphate ATP released from dying or damaged cells also causes NLRP3-inflammasome activation through either paracrine or autocrine sensing of ATP by the purinergic receptor P2X7 , — According to one model for this mode of activation, uptake of the crystalline and particulate matters into the cell causes lysosomal destabilization and release of cathepsin B, which is sensed by NLRP3 , Recent advances have put forward additional mechanisms underlying NLRP3-inflammasome activation.
Guanylate binding protein 5 GBP5 has been recently proposed as one such component that directly participates in NLRP3-inflammasome activation; however, further investigation is needed to decipher how the GBP5 is activated and why it is required for select inflammasome assembly Finally, studies by Munoz-Planillo et al. Production of mtROS often culminates in mitophagy, an autophagic clearance of dysfunctional mitochondria. Moreover, it has been recently suggested that autophagy may restrict NLRP3 activity by directly sequestering and targeting inflammasome components for degradation , Overall, it is reasonable to speculate that autophagy could serve as a mechanism for preventing excessive NLRP3-inflammasome activation , , — Mitochondrial dysfunction plays a central role in regulating the mechanisms involved in both inflammasome and apoptosis pathways.
Loss of mitochondrial membrane potential is a pivotal event in intrinsic apoptosis and is tightly regulated by the BCL2 family of proteins through a system of checks and balances Unlike their role in NOD signaling, initial studies have proposed that expression of these proteins might prevent caspasedependent cell death Overall, these studies place caspase and caspase-8 at the center of inflammasome activation; however, a general lack of consensus in the field makes it hard to aptly judge their contribution in inflammasome-induced inflammation.
Indeed, mice lacking NLRP3 have been shown to display exacerbated colonic inflammation upon DSS-induced colitis characterized by greater gut barrier damage, inflammatory immune cell infiltration, and cytokine production , In accord, a central role has been ascribed for caspase-1 and ASC in intestinal epithelial repair after DSS-injury Concomitantly, the increased colitogenic phenotype was completely reversed when mice were exogenously administered with the recombinant IL cytokine ,
The Role of Innate Immunity Receptors in the Pathogenesis of Inflammatory Bowel Disease
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. These results suggest that NOD2 not only has an immune stimulatory function, but also an immune regulatory function. Atherosclerosis is a chronic inflammatory disease of the arterial wall; its pathologic progression is highly dependent on the immune balance. This immune balance is regulated by infiltrating monocytes and macrophages, both of which express NOD2. These findings indicate a potential role of NOD2 in atherosclerosis.
Through peptidoglycan recognition, the nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2 enable detection of intracellular bacteria and promote their clearance through initiation of a pro-inflammatory transcriptional programme and other host defence pathways, including autophagy.
NOD proteins: regulators of inflammation in health and disease
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.
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.
NOD2 and inflammation: current insights
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. Elevated levels of blood cholesterol and vascular inflammation are considered as the primary triggers of cardiovascular disease due to atherosclerosis, a chronic disease of arteries [ 15 ]. Subsequent fatal events such as myocardial infarction are still responsible for the most illness-related fatalities worldwide [ 28 ].
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Mediators of Inflammation
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