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Immunoregulatory Receptor Signaling Networks 2.0

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

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 10771

Special Issue Editor


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Guest Editor
Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada
Interests: comparative immunology; immunoregulatory receptor-types; innate immunity; inflammation; intracellular signaling; macrophages; phagocytosis; teleost
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Special Issue Information

Dear Colleagues,

Innate immune cells (e.g., neutrophils, monocytes/macrophages, and natural killer cells) elicit potent effector responses capable of destroying a diverse range of invading pathogens. In general, these responses are controlled by immunoregulatory receptor-types that translate extracellular stimuli to complex, yet highly conserved, intracellular signaling networks. Depending on the immune cell-type and specific receptor activated, immunoregulatory signaling cascades trigger degranulation, phagocytosis, cell-mediated cytotoxicity, as well as the production of bioactive molecules. Prototypical immunoregulatory receptors are located in the plasma membrane, and structurally, they contain extracellular domains providing the interface for target recognition as well as transmembrane and cytoplasmic tail regions that can facilitate transmission of target binding into innate effector responses. Characteristically, these occur through a series of tyrosine-based and/or other intracellular biochemical signaling events. Generally, the broad classifications of immunoregulatory receptors as inhibitory or stimulatory have depended primarily on whether or not they contain key signaling motifs within their cytoplasmic regions (e.g., ITIMs and ITAMs). However, the functional outcome of immunoregulatory receptor engagement does not always precisely coincide with these canonical motifs, as alternative mechanisms of motif-dependent signaling events provide functional versatility among previously defined signaling networks. The magnitude and duration of receptor activation by natural ligands may also play a key role in the type of functional outcomes that occur following immunoregulatory receptor activation. In addition, the inherent modularity of signaling motifs within the transduction machinery allows for complex and novel regulatory behaviors to arise from relatively simple genetic events, such as recombination, deletion, or insertion. The heterogeneity observed within the intermolecular interactions between immunoregulatory receptor families (e.g., receptor crosstalk) also facilitates intricate tuning of responses through selective signaling dynamics. Finally, the presence of diverse immunoregulatory receptor families throughout immune cell lineages further compounds the apparent complexity required for the integrated control of innate immunity. In this Special Issue, we welcome reviews or data papers focused on understanding the dynamics of immunoregulatory receptor signaling networks using various vertebrate model systems. We also encourage the submission of papers describing new signaling pathways that further explore the versatility of immunoregulatory receptor signaling networks during inflammation.

Dr. James L. Stafford
Guest Editor

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Keywords

  • innate immunity
  • inflammation
  • tyrosine-based signaling motifs
  • phosphorylation
  • kinases
  • phosphatases
  • intracellular signaling cascades
  • immunoregulatory receptors
  • cytoplasmic tail regions
  • immunoregulatory receptor crosstalk

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Published Papers (2 papers)

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18 pages, 3427 KiB  
Article
Regulation of the Expression, Oligomerisation and Signaling of the Inhibitory Receptor CLEC12A by Cysteine Residues in the Stalk Region
by Julien Vitry, Guillaume Paré, Andréa Murru, Xavier Charest-Morin, Halim Maaroufi, Kenneth R. McLeish, Paul H. Naccache and Maria J. Fernandes
Int. J. Mol. Sci. 2021, 22(19), 10207; https://doi.org/10.3390/ijms221910207 - 22 Sep 2021
Cited by 5 | Viewed by 2464
Abstract
CLEC12A is a myeloid inhibitory receptor that negatively regulates inflammation in mouse models of autoimmune and autoinflammatory arthritis. Reduced CLEC12A expression enhances myeloid cell activation and inflammation in CLEC12A knock-out mice with collagen antibody-induced or gout-like arthritis. Similarly to other C-type lectin receptors, [...] Read more.
CLEC12A is a myeloid inhibitory receptor that negatively regulates inflammation in mouse models of autoimmune and autoinflammatory arthritis. Reduced CLEC12A expression enhances myeloid cell activation and inflammation in CLEC12A knock-out mice with collagen antibody-induced or gout-like arthritis. Similarly to other C-type lectin receptors, CLEC12A harbours a stalk domain between its ligand binding and transmembrane domains. While it is presumed that the cysteines in the stalk domain have multimerisation properties, their role in CLEC12A expression and/or signaling remain unknown. We thus used site-directed mutagenesis to determine whether the stalk domain cysteines play a role in CLEC12A expression, internalisation, oligomerisation, and/or signaling. Mutation of C118 blocks CLEC12A transport through the secretory pathway diminishing its cell-surface expression. In contrast, mutating C130 does not affect CLEC12A cell-surface expression but increases its oligomerisation, inducing ligand-independent phosphorylation of the receptor. Moreover, we provide evidence that CLEC12A dimerisation is regulated in a redox-dependent manner. We also show that antibody-induced CLEC12A cross-linking induces flotillin oligomerisation in insoluble membrane domains in which CLEC12A signals. Taken together, these data indicate that the stalk cysteines in CLEC12A differentially modulate this inhibitory receptor’s expression, oligomerisation and signaling, suggestive of the regulation of CLEC12A in a redox-dependent manner during inflammation. Full article
(This article belongs to the Special Issue Immunoregulatory Receptor Signaling Networks 2.0)
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44 pages, 3844 KiB  
Review
Innate Receptor Activation Patterns Involving TLR and NLR Synergisms in COVID-19, ALI/ARDS and Sepsis Cytokine Storms: A Review and Model Making Novel Predictions and Therapeutic Suggestions
by Robert Root-Bernstein
Int. J. Mol. Sci. 2021, 22(4), 2108; https://doi.org/10.3390/ijms22042108 - 20 Feb 2021
Cited by 83 | Viewed by 7748
Abstract
Severe COVID-19 is characterized by a “cytokine storm”, the mechanism of which is not yet understood. I propose that cytokine storms result from synergistic interactions among Toll-like receptors (TLR) and nucleotide-binding oligomerization domain-like receptors (NLR) due to combined infections of SARS-CoV-2 with other [...] Read more.
Severe COVID-19 is characterized by a “cytokine storm”, the mechanism of which is not yet understood. I propose that cytokine storms result from synergistic interactions among Toll-like receptors (TLR) and nucleotide-binding oligomerization domain-like receptors (NLR) due to combined infections of SARS-CoV-2 with other microbes, mainly bacterial and fungal. This proposition is based on eight linked types of evidence and their logical connections. (1) Severe cases of COVID-19 differ from healthy controls and mild COVID-19 patients in exhibiting increased TLR4, TLR7, TLR9 and NLRP3 activity. (2) SARS-CoV-2 and related coronaviruses activate TLR3, TLR7, RIG1 and NLRP3. (3) SARS-CoV-2 cannot, therefore, account for the innate receptor activation pattern (IRAP) found in severe COVID-19 patients. (4) Severe COVID-19 also differs from its mild form in being characterized by bacterial and fungal infections. (5) Respiratory bacterial and fungal infections activate TLR2, TLR4, TLR9 and NLRP3. (6) A combination of SARS-CoV-2 with bacterial/fungal coinfections accounts for the IRAP found in severe COVID-19 and why it differs from mild cases. (7) Notably, TLR7 (viral) and TLR4 (bacterial/fungal) synergize, TLR9 and TLR4 (both bacterial/fungal) synergize and TLR2 and TLR4 (both bacterial/fungal) synergize with NLRP3 (viral and bacterial). (8) Thus, a SARS-CoV-2-bacterium/fungus coinfection produces synergistic innate activation, resulting in the hyperinflammation characteristic of a cytokine storm. Unique clinical, experimental and therapeutic predictions (such as why melatonin is effective in treating COVID-19) are discussed, and broader implications are outlined for understanding why other syndromes such as acute lung injury, acute respiratory distress syndrome and sepsis display varied cytokine storm symptoms. Full article
(This article belongs to the Special Issue Immunoregulatory Receptor Signaling Networks 2.0)
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