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Special Issue "The Diversity of Mammalian Nod-Like Receptor Functions"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (31 December 2020).

Special Issue Editors

Dr. Szilvia Benko
Website
Guest Editor
Head of the Laboratory of Immunophysiology in the Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
Interests: NLR proteins; NLRP3 inflammasome; NLRC5, macrophage subtypes; innate immunity; cell signaling; gene expression
Prof. Thomas A. Kufer
Website
Guest Editor
Department of Immunology at the University of Hohenheim, Stuttgart, Germany.
Interests: NLR proteins; NOD1, NOD2, NLRC5, NLRP10; host–pathogen interactions; immunity; inflammation

Special Issue Information

Nod-like receptors (NLRs) form a family of intracellular pattern recognition receptors that were first described about 20 years ago. They show high domain similarity to the intracellular R proteins, which are responsible for disease resistance in plants, and to membrane-bound Toll-like receptors (TLRs) in animals and humans. The high homology to other well-described pattern recognition receptors quickly attracted attention. Intensive study of some NLR members revealed that NLRs sense a variety of microbial or stress molecules, can from inflammasomes, act as high-molecular weight signaling hubs, or regulate signal transduction pathways and gene expression. However, some NLRs also contribute to gametogenesis, fertility, embryonal development, and metabolism. Medical interest arose, with studies showing associations of polymorphisms in certain NLR-encoding genes with autoinflammatory and autoimmune diseases, hypersensitivity reactions, and cancer.

The NLR family contains more than 20 members in most mammals. However, research mainly focused on a handful of these proteins, the most prominent examples being NOD1, NOD2, and NLRP3. Beside these well-characterized NLRs, other members of the NLR family have received less attention, and the function of several human NLRs still remains elusive.

This Special Issue, “The Diversity of Mammalian Nod-like Receptor Functions”, invites original research and review articles that address aspects of NLR functions. We encourage submissions of work on non-inflammasome forming NLRs and on understudied inflammasomes and NLR members in human and other mammalian species, amongst others. This Special Issue aims to provide a timely overview of the knowns and unknows of NLR biology.

Dr. Szilvia Benko
Prof. Thomas A. Kufer
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • NLR
  • diseases
  • signaling
  • development
  • cell death
  • inflammation
  • cytokines
  • cancer
  • interferon
  • metabolism
  • innate immunity

Published Papers (11 papers)

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Review

Open AccessReview
The MHC Class-I Transactivator NLRC5: Implications to Cancer Immunology and Potential Applications to Cancer Immunotherapy
Int. J. Mol. Sci. 2021, 22(4), 1964; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041964 - 17 Feb 2021
Abstract
The immune system constantly monitors the emergence of cancerous cells and eliminates them. CD8+ cytotoxic T lymphocytes (CTLs), which kill tumor cells and provide antitumor immunity, select their targets by recognizing tumor antigenic peptides presented by MHC class-I (MHC-I) molecules. Cancer cells [...] Read more.
The immune system constantly monitors the emergence of cancerous cells and eliminates them. CD8+ cytotoxic T lymphocytes (CTLs), which kill tumor cells and provide antitumor immunity, select their targets by recognizing tumor antigenic peptides presented by MHC class-I (MHC-I) molecules. Cancer cells circumvent immune surveillance using diverse strategies. A key mechanism of cancer immune evasion is downregulation of MHC-I and key proteins of the antigen processing and presentation machinery (APM). Even though impaired MHC-I expression in cancers is well-known, reversing the MHC-I defects remains the least advanced area of tumor immunology. The discoveries that NLRC5 is the key transcriptional activator of MHC-I and APM genes, and genetic lesions and epigenetic modifications of NLRC5 are the most common cause of MHC-I defects in cancers, have raised the hopes for restoring MHC-I expression. Here, we provide an overview of cancer immunity mediated by CD8+ T cells and the functions of NLRC5 in MHC-I antigen presentation pathways. We describe the impressive advances made in understanding the regulation of NLRC5 expression, the data supporting the antitumor functions of NLRC5 and a few reports that argue for a pro-tumorigenic role. Finally, we explore the possible avenues of exploiting NLRC5 for cancer immunotherapy. Full article
(This article belongs to the Special Issue The Diversity of Mammalian Nod-Like Receptor Functions)
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Open AccessReview
Immunological Roles of NLR in Allergic Diseases and Its Underlying Mechanisms
Int. J. Mol. Sci. 2021, 22(4), 1507; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041507 - 03 Feb 2021
Abstract
Our understanding on the immunological roles of pathogen recognition in innate immunity has vastly increased over the past 20 years. Nucleotide-binding oligomerization domain (NOD)-like receptors (NLR) are cytosolic pattern recognition receptors (PRR) that are responsible for sensing microbial motifs and endogenous damage signals [...] Read more.
Our understanding on the immunological roles of pathogen recognition in innate immunity has vastly increased over the past 20 years. Nucleotide-binding oligomerization domain (NOD)-like receptors (NLR) are cytosolic pattern recognition receptors (PRR) that are responsible for sensing microbial motifs and endogenous damage signals in mammalian cytosol for immune surveillance and host defense. The accumulating discoveries on these NLR sensors in allergic diseases suggest that the pathogenesis of allergic diseases may not be confined to the adaptive immune response. Therapy targeting NLR in murine models also shields light on its potential in the treatment of allergies in man. In this review, we herein summarize the recent understanding of the role of NLR sensors and their molecular mechanisms involved in allergic inflammation, including atopic dermatitis and allergic asthma. Full article
(This article belongs to the Special Issue The Diversity of Mammalian Nod-Like Receptor Functions)
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Open AccessReview
Regulation, Activation and Function of Caspase-11 during Health and Disease
Int. J. Mol. Sci. 2021, 22(4), 1506; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041506 - 03 Feb 2021
Abstract
Caspase-11 is a pro-inflammatory enzyme that is stringently regulated during its expression and activation. As caspase-11 is not constitutively expressed in cells, it requires a priming step for its upregulation, which occurs following the stimulation of pathogen and cytokine receptors. Once expressed, caspase-11 [...] Read more.
Caspase-11 is a pro-inflammatory enzyme that is stringently regulated during its expression and activation. As caspase-11 is not constitutively expressed in cells, it requires a priming step for its upregulation, which occurs following the stimulation of pathogen and cytokine receptors. Once expressed, caspase-11 activation is triggered by its interaction with lipopolysaccharide (LPS) from Gram-negative bacteria. Being an initiator caspase, activated caspase-11 functions primarily through its cleavage of key substrates. Gasdermin D (GSDMD) is the primary substrate of caspase-11, and the GSDMD cleavage fragment generated is responsible for the inflammatory form of cell death, pyroptosis, via its formation of pores in the plasma membrane. Thus, caspase-11 functions as an intracellular sensor for LPS and an immune effector. This review provides an overview of caspase-11—describing its structure and the transcriptional mechanisms that govern its expression, in addition to its activation, which is reported to be regulated by factors such as guanylate-binding proteins (GBPs), high mobility group box 1 (HMGB1) protein, and oxidized phospholipids. We also discuss the functional outcomes of caspase-11 activation, which include the non-canonical inflammasome, modulation of actin dynamics, and the initiation of blood coagulation, highlighting the importance of inflammatory caspase-11 during infection and disease. Full article
(This article belongs to the Special Issue The Diversity of Mammalian Nod-Like Receptor Functions)
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Open AccessReview
Focusing on the Cell Type Specific Regulatory Actions of NLRX1
Int. J. Mol. Sci. 2021, 22(3), 1316; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031316 - 28 Jan 2021
Abstract
Cells utilize a diverse repertoire of cell surface and intracellular receptors to detect exogenous or endogenous danger signals and even the changes of their microenvironment. However, some cytosolic NOD-like receptors (NLR), including NLRX1, serve more functions than just being general pattern recognition receptors. [...] Read more.
Cells utilize a diverse repertoire of cell surface and intracellular receptors to detect exogenous or endogenous danger signals and even the changes of their microenvironment. However, some cytosolic NOD-like receptors (NLR), including NLRX1, serve more functions than just being general pattern recognition receptors. The dynamic translocation between the cytosol and the mitochondria allows NLRX1 to interact with many molecules and thereby to control multiple cellular functions. As a regulatory NLR, NLRX1 fine-tunes inflammatory signaling cascades, regulates mitochondria-associated functions, and controls metabolism, autophagy and cell death. Nevertheless, literature data are inconsistent and often contradictory regarding its effects on individual cellular functions. One plausible explanation might be that the regulatory effects of NLRX1 are highly cell type specific and the features of NLRX1 mediated regulation might be determined by the unique functional activity or metabolic profile of the given cell type. Here we review the cell type specific actions of NLRX1 with a special focus on cells of the immune system. NLRX1 has already emerged as a potential therapeutic target in numerous immune-related diseases, thus we aim to highlight which regulatory properties of NLRX1 are manifested in disease-associated dominant immune cells that presumably offer promising therapeutic solutions to treat these disorders. Full article
(This article belongs to the Special Issue The Diversity of Mammalian Nod-Like Receptor Functions)
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Open AccessReview
Role of NLRs in the Regulation of Type I Interferon Signaling, Host Defense and Tolerance to Inflammation
Int. J. Mol. Sci. 2021, 22(3), 1301; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031301 - 28 Jan 2021
Abstract
Type I interferon signaling contributes to the development of innate and adaptive immune responses to either viruses, fungi, or bacteria. However, amplitude and timing of the interferon response is of utmost importance for preventing an underwhelming outcome, or tissue damage. While several pathogens [...] Read more.
Type I interferon signaling contributes to the development of innate and adaptive immune responses to either viruses, fungi, or bacteria. However, amplitude and timing of the interferon response is of utmost importance for preventing an underwhelming outcome, or tissue damage. While several pathogens evolved strategies for disturbing the quality of interferon signaling, there is growing evidence that this pathway can be regulated by several members of the Nod-like receptor (NLR) family, although the precise mechanism for most of these remains elusive. NLRs consist of a family of about 20 proteins in mammals, which are capable of sensing microbial products as well as endogenous signals related to tissue injury. Here we provide an overview of our current understanding of the function of those NLRs in type I interferon responses with a focus on viral infections. We discuss how NLR-mediated type I interferon regulation can influence the development of auto-immunity and the immune response to infection. Full article
(This article belongs to the Special Issue The Diversity of Mammalian Nod-Like Receptor Functions)
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Open AccessReview
The NLRP3 Inflammasome and Its Role in the Pathogenicity of Leukemia
Int. J. Mol. Sci. 2021, 22(3), 1271; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031271 - 28 Jan 2021
Abstract
Chronic inflammation contributes to the development and progression of various tumors. Especially where the inflammation is mediated by cells of the innate immune system, the NLRP3 inflammasome plays an important role, as it senses and responds to a variety of exogenous and endogenous [...] Read more.
Chronic inflammation contributes to the development and progression of various tumors. Especially where the inflammation is mediated by cells of the innate immune system, the NLRP3 inflammasome plays an important role, as it senses and responds to a variety of exogenous and endogenous pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). The NLRP3 inflammasome is responsible for the maturation and secretion of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18 and for the induction of a type of inflammatory cell death known as pyroptosis. Overactivation of the NLRP3 inflammasome can be a driver of various diseases. Since leukemia is known to be an inflammation-driven cancer and IL-1β is produced in elevated levels by leukemic cells, research on NLRP3 in the context of leukemia has increased in recent years. In this review, we summarize the current knowledge on leukemia-promoting inflammation and, in particular, the role of the NLRP3 inflammasome in different types of leukemia. Furthermore, we examine a connection between NLRP3, autophagy and leukemia. Full article
(This article belongs to the Special Issue The Diversity of Mammalian Nod-Like Receptor Functions)
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Open AccessReview
Mediators of Metabolism: An Unconventional Role for NOD1 and NOD2
Int. J. Mol. Sci. 2021, 22(3), 1156; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031156 - 25 Jan 2021
Abstract
In addition to their classical roles as bacterial sensors, NOD1 and NOD2 have been implicated as mediators of metabolic disease. Increased expression of NOD1 and/or NOD2 has been reported in a range of human metabolic diseases, including obesity, diabetes, non-alcoholic fatty liver disease, [...] Read more.
In addition to their classical roles as bacterial sensors, NOD1 and NOD2 have been implicated as mediators of metabolic disease. Increased expression of NOD1 and/or NOD2 has been reported in a range of human metabolic diseases, including obesity, diabetes, non-alcoholic fatty liver disease, and metabolic syndrome. Although NOD1 and NOD2 share intracellular signaling pathway components, they are differentially upregulated on a cellular level and have opposing impacts on metabolic disease development in mouse models. These NOD-like receptors may directly mediate signaling downstream of cell stressors, such as endoplasmic reticulum stress and calcium influx, or in response to metabolic signals, such as fatty acids and glucose. Other studies suggest that stimulation of NOD1 or NOD2 by their bacterial ligands can result in inflammation, altered insulin responses, increased reactive oxygen signaling, and mitochondrial dysfunction. The activating stimuli for NOD1 and NOD2 in the context of metabolic disease are controversial and may be a combination of both metabolic and circulating bacterial ligands. In this review, we will summarize the current knowledge of how NOD1 and NOD2 may mediate metabolism in health and disease, as well as highlight areas of future investigation. Full article
(This article belongs to the Special Issue The Diversity of Mammalian Nod-Like Receptor Functions)
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Open AccessReview
The MHC Class II Transactivator CIITA: Not (Quite) the Odd-One-Out Anymore among NLR Proteins
Int. J. Mol. Sci. 2021, 22(3), 1074; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031074 - 22 Jan 2021
Abstract
In this review, we discuss the major histocompatibility complex (MHC) class II transactivator (CIITA), which is the master regulator of MHC class II gene expression. CIITA is the founding member of the mammalian nucleotide-binding and leucine-rich-repeat (NLR) protein family but stood apart for [...] Read more.
In this review, we discuss the major histocompatibility complex (MHC) class II transactivator (CIITA), which is the master regulator of MHC class II gene expression. CIITA is the founding member of the mammalian nucleotide-binding and leucine-rich-repeat (NLR) protein family but stood apart for a long time as the only transcriptional regulator. More recently, it was found that its closest homolog, NLRC5 (NLR protein caspase activation and recruitment domain (CARD)-containing 5), is a regulator of MHC-I gene expression. Both act as non-DNA-binding activators through multiple protein–protein interactions with an MHC enhanceosome complex that binds cooperatively to a highly conserved combinatorial cis-acting module. Thus, the regulation of MHC-II expression is regulated largely through the differential expression of CIITA. In addition to the well-defined role of CIITA in MHC-II GENE regulation, we will discuss several other aspects of CIITA functions, such as its role in cancer, its role as a viral restriction element contributing to intrinsic immunity, and lastly, its very recently discovered role as an inhibitor of Ebola and SARS-Cov-2 virus replication. We will briefly touch upon the recently discovered role of NLRP3 as a transcriptional regulator, which suggests that transcriptional regulation is, after all, not such an unusual feature for NLR proteins. Full article
(This article belongs to the Special Issue The Diversity of Mammalian Nod-Like Receptor Functions)
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Open AccessReview
Advances in Understanding Activation and Function of the NLRC4 Inflammasome
Int. J. Mol. Sci. 2021, 22(3), 1048; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031048 - 21 Jan 2021
Abstract
Innate immune receptors initiate a host immune response, or inflammatory response, upon detecting pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Among the innate immune receptors, nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) play a pivotal role in detecting cytosolic PAMPs and DAMPs. [...] Read more.
Innate immune receptors initiate a host immune response, or inflammatory response, upon detecting pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Among the innate immune receptors, nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) play a pivotal role in detecting cytosolic PAMPs and DAMPs. Some NLRs can form a multiprotein cytosolic complex known as the inflammasome. Inflammasome activation triggers caspase-1–mediated cleavage of the pore-forming protein gasdermin D (GSDMD), which drives a form of inflammatory cell death called pyroptosis. Parallelly, activated caspase-1 cleaves immature cytokines pro–IL-1β and pro–IL-18 into their active forms, which can be released via GSDMD membrane pores. The NLR family apoptosis inhibitory proteins (NAIP)-NLR family caspase-associated recruitment domain-containing protein 4 (NLRC4) inflammasome is important for mounting an immune response against Gram-negative bacteria. NLRC4 is activated through NAIPs sensing type 3 secretion system (T3SS) proteins from Gram-negative bacteria, such as Salmonella Typhimurium. Mutations in NAIPs and NLRC4 are linked to autoinflammatory disorders in humans. In this review, we highlight the role of the NAIP/NLRC4 inflammasome in host defense, autoinflammatory diseases, cancer, and cell death. We also discuss evidence pointing to a role of NLRC4 in PANoptosis, which was recently identified as a unique inflammatory programmed cell death pathway with important physiological relevance in a range of diseases. Improved understanding of the NLRC4 inflammasome and its potential roles in PANoptosis paves the way for identifying new therapeutic strategies to target disease. Full article
(This article belongs to the Special Issue The Diversity of Mammalian Nod-Like Receptor Functions)
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Open AccessReview
Detection of Bacterial Membrane Vesicles by NOD-Like Receptors
Int. J. Mol. Sci. 2021, 22(3), 1005; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031005 - 20 Jan 2021
Abstract
Bacterial membrane vesicles (BMVs) are nanoparticles produced by both Gram-negative and Gram-positive bacteria that can function to modulate immunity in the host. Both outer membrane vesicles (OMVs) and membrane vesicles (MVs), which are released by Gram-negative and Gram-positive bacteria, respectively, contain cargo derived [...] Read more.
Bacterial membrane vesicles (BMVs) are nanoparticles produced by both Gram-negative and Gram-positive bacteria that can function to modulate immunity in the host. Both outer membrane vesicles (OMVs) and membrane vesicles (MVs), which are released by Gram-negative and Gram-positive bacteria, respectively, contain cargo derived from their parent bacterium, including immune stimulating molecules such as proteins, lipids and nucleic acids. Of these, peptidoglycan (PG) and lipopolysaccharide (LPS) are able to activate host innate immune pattern recognition receptors (PRRs), known as NOD-like receptors (NLRs), such as nucleotide-binding oligomerisation domain-containing protein (NOD) 1, NOD2 and NLRP3. NLR activation is a key driver of inflammation in the host, and BMVs derived from both pathogenic and commensal bacteria have been shown to package PG and LPS in order to modulate the host immune response using NLR-dependent mechanisms. Here, we discuss the packaging of immunostimulatory cargo within OMVs and MVs, their detection by NLRs and the cytokines produced by host cells in response to their detection. Additionally, commensal derived BMVs are thought to shape immunity and contribute to homeostasis in the gut, therefore we also highlight the interactions of commensal derived BMVs with NLRs and their roles in limiting inflammatory diseases. Full article
(This article belongs to the Special Issue The Diversity of Mammalian Nod-Like Receptor Functions)
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Open AccessReview
Transcriptional Regulation of Inflammasomes
Int. J. Mol. Sci. 2020, 21(21), 8087; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218087 - 29 Oct 2020
Cited by 1
Abstract
Inflammasomes are multimolecular complexes with potent inflammatory activity. As such, their activity is tightly regulated at the transcriptional and post-transcriptional levels. In this review, we present the transcriptional regulation of inflammasome genes from sensors (e.g., NLRP3) to substrates (e.g., IL-1β). Lineage-determining transcription factors [...] Read more.
Inflammasomes are multimolecular complexes with potent inflammatory activity. As such, their activity is tightly regulated at the transcriptional and post-transcriptional levels. In this review, we present the transcriptional regulation of inflammasome genes from sensors (e.g., NLRP3) to substrates (e.g., IL-1β). Lineage-determining transcription factors shape inflammasome responses in different cell types with profound consequences on the responsiveness to inflammasome-activating stimuli. Pro-inflammatory signals (sterile or microbial) have a key transcriptional impact on inflammasome genes, which is largely mediated by NF-κB and that translates into higher antimicrobial immune responses. Furthermore, diverse intrinsic (e.g., circadian clock, metabolites) or extrinsic (e.g., xenobiotics) signals are integrated by signal-dependent transcription factors and chromatin structure changes to modulate transcriptionally inflammasome responses. Finally, anti-inflammatory signals (e.g., IL-10) counterbalance inflammasome genes induction to limit deleterious inflammation. Transcriptional regulations thus appear as the first line of inflammasome regulation to raise the defense level in front of stress and infections but also to limit excessive or chronic inflammation. Full article
(This article belongs to the Special Issue The Diversity of Mammalian Nod-Like Receptor Functions)
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