High expression of nucleotide-binding oligomerization domain protein 1 correlates with poor prognosis and immune cell infiltration in Glioblastoma Multiforme patients
0
Citation
45
Reference
10
Related Paper
Abstract:
Nucleotide-binding oligomerization domain protein 1 (NOD1) is one of the innate immune receptors that has been associated with tumorigenesis and abnormally expressed in various cancers. However, the role of NOD1 in Glioblastoma Multiforme (GBM) has not been investigated. We used the Tumor Immune Estimate Resource (TIMER) database to compare the differential expression of NOD1 in various tumors. NOD1 expression in GBM was further validated in the GEO database, and the survival of NOD1 was assessed by the Kaplan–Meier method. Clinical samples were collected to validate NOD1 expression. GSEA was carried out to expound on NOD1-related pathways involved in GBM. NOD1 co-expression and enrichment analysis were performed using the Linked Omics database and R software. The relationship between immune infiltrates and NOD1 expression was assessed by TIMER. Besides, the correlation between NOD1 and immune signatures (immunomodulators and chemokine) was evaluated by TISIDB. We found that NOD1 expression was significantly upregulated in GBM patients, and higher expression of NOD1 was associated with a poor prognosis. GSEA and enrichment analysis revealed that NOD1 might play a vital role in immune response and GBM progression. TIMER analysis showed a positive correlation between NOD1 expression and 17 types of tumor-infiltrating immune cells. Moreover, NOD1 expression was positively correlated with the expression of chemokine and immunomodulators in GBM. Overall, our findings suggest that NOD1 is a promising prognostic biomarker and is associated with immune cell infiltration in GBM, making it a potential diagnostic biomarker for this aggressive brain cancer.Keywords:
NOD1
Innate immune detection of pathogens relies on specific classes of microbial sensors called pattern-recognition molecules (PRM). In mammals, such PRM include Toll-like receptors (TLRs) and the intracellular proteins NOD1 and NOD2, which belong to the family of Nod-like receptors (NLRs). Over the last decade as these molecules were discovered, a function in innate immunity has been assigned for the majority of them and, for most, the microbial motifs that these molecules detect were identified. One of the next challenges in innate immunity is to establish a better understanding of the complex interplay between signaling pathways induced simultaneously by distinct PRMs and how this affects tailoring first-line responses and the induction of adaptive immunity to a given pathogen.
NOD1
Intrinsic immunity
Pathogen-associated molecular pattern
Cite
Citations (78)
NOD1
Cite
Citations (53)
Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is an intracellular pattern recognition receptor that recognizes bacterial peptidoglycan (PG) containing meso-diaminopimelic acid (mesoDAP) and activates the innate immune system. Interestingly, a few pathogenic and commensal bacteria modify their PG stem peptide by amidation of mesoDAP (mesoDAPNH2). In the present study, NOD1 stimulation assays were performed using bacterial PG containing mesoDAP (PGDAP) and mesoDAPNH2 (PGDAPNH2) to understand the differences in their biomolecular recognition mechanism. PGDAP was effectively recognized, whereas PGDAPNH2 showed reduced recognition by the NOD1 receptor. Restimulation of the NOD1 receptor, which was initially stimulated with PGDAP using PGDAPNH2, did not show any further NOD1 activation levels than with PGDAP alone. But the NOD1 receptor initially stimulated with PGDAPNH2 responded effectively to restimulation with PGDAP. The biomolecular structure–recognition relationship of the ligand-sensing leucine-rich repeat (LRR) domain of human NOD1 (NOD1–LRR) with PGDAP and PGDAPNH2 was studied by different computational techniques to further understand the molecular basis of our experimental observations. The d-Glu–mesoDAP motif of GMTPDAP, which is the minimum essential motif for NOD1 activation, was found involved in specific interactions at the recognition site, but the interactions of the corresponding d-Glu–mesoDAP motif of PGDAPNH2 occur away from the recognition site of the NOD1 receptor. Hot-spot residues identified for effective PG recognition by NOD1–LRR include W820, G821, D826 and N850, which are evolutionarily conserved across different host species. These integrated results thus successfully provided the atomic level and biochemical insights on how PGs containing mesoDAPNH2 evade NOD1–LRR receptor recognition.
NOD1
Diaminopimelic acid
Cite
Citations (36)
The importance of peptidoglycan detection in the host innate immune response has long been underestimated. However, the recent identification of proteins involved in the sensing of peptidoglycan in both mammals and Drosophila has revealed that the detection of this microbial motif is key to the defense response. In Drosophila, the peptidoglycan-recognition proteins (PGRP) are the initial sensors of infecting bacteria that then trigger a cascade ultimately leading to the expression of antimicrobial peptides. In mammals, PGRP also exist and although they bind peptidoglycan, the role of these proteins in innate immune responses remains to be clearly defined. In contrast, the Nod proteins (Nod1 and Nod2), which are also involved in peptidoglycan sensing, appear to play a key role in innate immunity against bacteria by triggering host defense responses through the activation of the transcription factor, NF-kappaB. Interestingly, mutations in Nod2 are related to increased susceptibility to Crohn's disease, thereby implicating defective bacterial sensing in the development at this chronic disease. In this review, we will focus on the recent findings concerning mammalian and Drosophila proteins involved in peptidoglycan recognition and the putative role of these proteins in the innate immune defense response.
NOD1
Cite
Citations (136)
Microglia Stimulate the Invasiveness of Glioma Cells by Increasing the Activity of Metalloprotease-2
Gliomas represent the most frequent type of human brain tumor, and their strong invasiveness is a significant clinical problem. Microglia, the immunocompetent cells of the brain, contribute significantly to the tumor and are potential interaction partners of the glioma cells. We studied the impact of the presence of microglia on tumor cell invasion in cultured brain slices. To selectively deplete microglia, the slices were treated with clodronate-filled liposomes. When glioma cells were injected into slices devoid of endogenous microglia, the invasiveness of the tumors was significantly decreased as compared with controls. Inoculation of exogenous microglia together with glioma cells into cultured brain slices increased the infiltrative behavior of the tumor depending on the microglia/glioma cell ratio. Cell culture experiments revealed that soluble factors released from glioma cells strongly stimulate metalloprotease-2 activity in microglia. In the brain slices inoculated with glioma cells, increased activity of metalloprotease-2 was directly correlated with the abundance of microglia. Our data indicate that glioma cells stimulate microglial cells to increase breakdown of extracellular matrix and thereby promote tumor invasiveness.
U87
Neuroglia
Cite
Citations (289)
Neuroglia
Cite
Citations (6)
Cell surface innate immune receptors can directly detect a variety of extracellular pathogens to which cytoplasmic innate immune sensors are rarely exposed. Instead, within the cytoplasm, the environment is rife with cellular machinery and signaling pathways that are indirectly perturbed by pathogenic microbes to activate intracellular sensors, such as pyrin, NLRP1, NLRP3, or NLRC4. Therefore, subtle changes in key intracellular processes such as phosphorylation, ubiquitination, and other pathways leading to posttranslational protein modification are key determinants of innate immune recognition in the cytoplasm. This concept is critical to establish the “guard hypothesis” whereby otherwise homeostatic pathways that keep innate immune sensors at bay are released in response to alterations in their posttranslational modification status. Originally identified in plants, evidence that a similar guardlike mechanism exists in humans has recently been identified, whereby a mutation that prevents phosphorylation of the innate immune sensor pyrin triggers a dominantly inherited autoinflammatory disease. It is also noteworthy that even when a cytoplasmic innate immune sensor has a direct ligand, such as bacterial peptidoglycan (NOD1 or NOD2), RNA (RIG-I or MDA5), or DNA (cGAS or IFI16), it can still be influenced by posttranslational modification to dramatically alter its response. Therefore, due to their existence in the cytoplasmic milieu, posttranslational modification is a key determinant of intracellular innate immune receptor functionality.
Pyrin domain
NOD1
Cite
Citations (69)
Kawasaki disease (KD) is an acute self-limited systemic vasculitis, and could develop in association with innate immune disorders. An innate immune system appears to play a key role in the development of KD, because pathogen-associated molecular patterns(PAMPs) and damage-associated molecular patterns(DAMPs) are elevated in the sera at acute phase KD, and oral administration of innate immune Nod1 ligand induces KD-like coronary arteritis in mice. PAMPs can be produced massively from microbes in a certain condition. DAMPs are produced from the host cells by the stimulation of PAMPs. We propose a hypothesis that PAMPs and DAMPs activate innate immune system and vascular cells through innate immune pattern recognition receptors(PRR) to release chemokines and cytokines, and induce KD in genetically predisposed individuals.
NOD1
Innate lymphoid cell
CCL18
Pathogen-associated molecular pattern
Cite
Citations (7)
Innate immune detection of pathogens relies on specific classes of microbial sensors called pattern-recognition molecules (PRM). In mammals, such PRM include Toll-like receptors (TLRs) and the intracellular proteins NOD1 and NOD2, which belong to the family of Nod-like receptors (NLRs). Over the last decade as these molecules were discovered, a function in innate immunity has been assigned for the majority of them and, for most, the microbial motifs that these molecules detect were identified. One of the next challenges in innate immunity is to establish a better understanding of the complex interplay between signaling pathways induced simultaneously by distinct PRMs and how this affects tailoring first-line responses and the induction of adaptive immunity to a given pathogen.
NOD1
Intrinsic immunity
Pathogen-associated molecular pattern
Cite
Citations (44)
Author(s): Rice, Rachel Anne | Advisor(s): Green, Kim N | Abstract: Microglia are the immune competent cells of the central nervous system (CNS). During development, microglia play critical roles in pruning synapses and refining neuronal connectivity. In the adult brain, microglia constantly survey the parenchyma for cellular damage or invading pathogens. Upon detection of such events, microglia become activated and shift to a phagocytic phenotype, secreting pro-inflammatory molecules and adopting an amoeboid morphology. As part of the resolution/repair process, microglia return to a surveillant state and produce anti-inflammatory molecules. Unfortunately, with severe insults, such as traumatic brain injury or chronic neurodegeneration, microglia remain activated and contribute to an inflammatory process that is never, or poorly, resolved. In this way, we hypothesize that microglia contribute deleteriously to functional outcomes.The goal of my dissertation is to determine the contributions of microglia to neuronal health and cognition in both the healthy and injured brain. The direct assessment of microglia-specific contributions is possible due to the discovery by our lab that microglia are dependent upon signaling through the colony-stimulating factor 1 receptor (CSF1R) for their survival. Treatment with a small-molecule CSF1R inhibitor eliminates g99% of microglia from the adult mouse brain. Critically, microglia fully repopulate the CNS upon withdrawal of the CSF1R inhibitor, effectively renewing this cellular compartment. Using a genetic model of inducible neuronal loss, I have determined that the elimination of microglia during a lesion is detrimental to cellular health, while the elimination of microglia following a lesion results in the reversal of many lesion-induced deficits. Importantly, this research suggests that the microglia-mediated immune response is beneficial during insult or injury, but deleterious after such an event. Moreover, repopulation of the brain with new microglia following neuronal lesioning largely resets the inflammatory milieu and confers functional benefits.Finally, long-term elimination of microglia was employed in order to determine if these cells shape the synaptic landscape in the healthy adult brain, as they do during development. Indeed, I found that microglial elimination in healthy adult mice results in brain-wide and robust increases in dendritic spine numbers and excitatory neuronal connectivity, indicating that microglia modulate synaptic function throughout the course of the lifetime.
Synaptic Pruning
Cite
Citations (0)