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Special Issue "Immunoregulatory Receptor Signaling Networks"

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: 31 May 2020.

Special Issue Editor

Dr. James L. Stafford
Website
Guest Editor
Department of Biological Sciences, University of Alberta, Edmonton, Canada
Interests: comparative immunology; immunoregulatory receptor-types; innate immunity; inflammation; intracellular signaling; macrophages; phagocytosis; teleost

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

Manuscript Submission Information

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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

Published Papers (4 papers)

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Research

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Open AccessArticle
Nasal Epithelial Cells Activated with Alternaria and House Dust Mite Induce Not Only Th2 but Also Th1 Immune Responses
Int. J. Mol. Sci. 2020, 21(8), 2693; https://doi.org/10.3390/ijms21082693 - 13 Apr 2020
Abstract
Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by mucosal inflammation. Airborne allergens are associated with upper and lower airway inflammatory disease. We investigated the effects of airborne allergen stimulation in the nasal epithelial cells and their effect on the peripheral blood mononuclear [...] Read more.
Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by mucosal inflammation. Airborne allergens are associated with upper and lower airway inflammatory disease. We investigated the effects of airborne allergen stimulation in the nasal epithelial cells and their effect on the peripheral blood mononuclear cells’ (PBMCs) Th immune polarization. Interleukin (IL)-10, IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) levels were determined using the enzyme-linked immunosorbent assay (ELISA) in nasal polyp tissues. Cultured primary nasal epithelial cells were stimulated with Alternaria alternata, Aspergillus fumigatus, Dermatophagoides pteronyssinus (DP), and Dermatophagoides farina (DF) for 48 hours. IL-6, IL-25, IL-33, and TSLP production were measured by ELISA, and the nuclear factor-κB (NF-κB), activator protein 1 (AP-1), and mitogen-activated protein kinase (MAPK) expression were determined by western blot analyses. PBMCs were cultured with nasal epithelial cell-conditioned media (NECM), and IL-5, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α were measured. Innate lymphoid type2 cells (ILC2) were analyzed with flowcytometry. IL-25, IL-33, and TSLP levels were significantly higher in eosinophilic nasal polyps. Alternaria, DP, and DF enhanced IL-33 and TSLP production from the nasal epithelial cells through the NF-κB, AP-1, and MAPK pathway. NECM induced IL-5, IFN-γ, and TNF-α production from PBMCs, without increasing ILC2 expression. Alternaria and house dust mites enhanced the chemical mediator production from nasal epithelial cells and these allergens may induce not only Th2 inflammatory responses but also Th1 inflammatory responses in the nasal mucosa. Full article
(This article belongs to the Special Issue Immunoregulatory Receptor Signaling Networks)
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Open AccessArticle
Protective Effects of Recombinant Human Soluble Thrombomodulin on Lipopolysaccharide-Induced Acute Kidney Injury
Int. J. Mol. Sci. 2020, 21(7), 2519; https://doi.org/10.3390/ijms21072519 - 05 Apr 2020
Abstract
Thrombomodulin (TM) is a single transmembrane, multidomain glycoprotein receptor for thrombin, and is best known for its role as a cofactor in a clinically important natural anticoagulant pathway. In addition to its anticoagulant function, TM has well-defined anti-inflammatory properties. Soluble TM levels increase [...] Read more.
Thrombomodulin (TM) is a single transmembrane, multidomain glycoprotein receptor for thrombin, and is best known for its role as a cofactor in a clinically important natural anticoagulant pathway. In addition to its anticoagulant function, TM has well-defined anti-inflammatory properties. Soluble TM levels increase significantly in the plasma of septic patients; however, the possible involvement of recombinant human soluble TM (rTM) transduction in the pathogenesis of lipopolysaccharide (LPS)-induced nephrotoxicity, including acute kidney injury (AKI), has remained unclear. Mice were injected intraperitoneally with 15 mg/kg LPS. rTM (3 mg/kg) or saline was administered to the animals before the 3 and 24 h LPS-injection. At 24 and 48 h, blood urea nitrogen, the inflammatory cytokines in sera and kidney, and histological findings were assessed. Cell activation and apoptosis signal was assessed by Western blot analysis. In this study using a mouse model of LPS-induced AKI, we found that rTM attenuated renal damage by reducing both cytokine and cell activation and apoptosis signals with the accumulation of CD4+ T-cells, CD11c+ cells, and F4/80+ cells via phospho c-Jun activations and Bax expression. These findings suggest that the mechanism underlying these effects of TM may be mediated by a reduction in inflammatory cytokine production in response to LPS. These molecules might thereby provide a new therapeutic strategy in the context of AKI with sepsis. Full article
(This article belongs to the Special Issue Immunoregulatory Receptor Signaling Networks)
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Open AccessArticle
Anti-Inflammatory and Anti-Migratory Activities of Isoquinoline-1-Carboxamide Derivatives in LPS-Treated BV2 Microglial Cells via Inhibition of MAPKs/NF-κB Pathway
Int. J. Mol. Sci. 2020, 21(7), 2319; https://doi.org/10.3390/ijms21072319 - 27 Mar 2020
Abstract
Eleven novel isoquinoline-1-carboxamides (HSR1101~1111) were synthesized and evaluated for their effects on lipopolysaccharide (LPS)-induced production of pro-inflammatory mediators and cell migration in BV2 microglial cells. Three compounds (HSR1101~1103) exhibited the most potent suppression of LPS-induced pro-inflammatory mediators, including interleukin (IL)-6, tumor necrosis factor-alpha, [...] Read more.
Eleven novel isoquinoline-1-carboxamides (HSR1101~1111) were synthesized and evaluated for their effects on lipopolysaccharide (LPS)-induced production of pro-inflammatory mediators and cell migration in BV2 microglial cells. Three compounds (HSR1101~1103) exhibited the most potent suppression of LPS-induced pro-inflammatory mediators, including interleukin (IL)-6, tumor necrosis factor-alpha, and nitric oxide (NO), without significant cytotoxicity. Among them, only N-(2-hydroxyphenyl) isoquinoline-1-carboxamide (HSR1101) was found to reverse LPS-suppressed anti-inflammatory cytokine IL-10, so it was selected for further characterization. HSR1101 attenuated LPS-induced expression of inducible NO synthase and cyclooxygenase-2. Particularly, HSR1101 abated LPS-induced nuclear translocation of NF-κB through inhibition of IκB phosphorylation. Furthermore, HSR1101 inhibited LPS-induced cell migration and phosphorylation of mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase, and p38 MAPK. The specific MAPK inhibitors, U0126, SP600125, and SB203580, suppressed LPS-stimulated pro-inflammatory mediators, cell migration, and NF-κB nuclear translocation, indicating that MAPKs may be the upstream kinase of NF-κB signaling. Collectively, these results demonstrate that HSR1101 is a potent and promising compound suppressing LPS-induced inflammation and cell migration in BV2 microglial cells, and that inhibition of the MAPKs/NF-κB pathway mediates its anti-inflammatory and anti-migratory effects. Based on our findings, HSR1101 may have beneficial impacts on various neurodegenerative disorders associated with neuroinflammation and microglial activation. Full article
(This article belongs to the Special Issue Immunoregulatory Receptor Signaling Networks)
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Review

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Open AccessReview
Immunoregulatory Property of C-Type Lectin-Like Receptors in Fibrosing Interstitial Lung Diseases
Int. J. Mol. Sci. 2020, 21(10), 3665; https://doi.org/10.3390/ijms21103665 - 22 May 2020
Abstract
The innate immune system identifies exogenous threats or endogenous stress through germline-encoded receptors called pattern recognition receptors (PRRs) that initiate consecutive downstream signaling pathways to control immune responses. However, the contribution of the immune system and inflammation to fibrosing interstitial lung diseases (ILD) [...] Read more.
The innate immune system identifies exogenous threats or endogenous stress through germline-encoded receptors called pattern recognition receptors (PRRs) that initiate consecutive downstream signaling pathways to control immune responses. However, the contribution of the immune system and inflammation to fibrosing interstitial lung diseases (ILD) remains poorly understood. Immunoreceptor tyrosine-based motif-bearing C-type lectin-like receptors (CTLRs) may interact with various immune cells during tissue injury and wound repair processes. Dectin-1 is a CTLR with dominant mechanisms manifested through its intracellular signaling cascades, which regulate fibrosis-promoting properties through gene transcription and cytokine activation. Additionally, immune impairment in ILD facilitates microbiome colonization; hence, Dectin-1 is the master protector in host pulmonary defense against fungal invasion. Recent progress in determining the signaling pathways that control the balance of fibrosis has implicated immunoreceptor tyrosine-based motif-bearing CTLRs as being involved, either directly or indirectly, in the pathogenesis of fibrosing ILD. Full article
(This article belongs to the Special Issue Immunoregulatory Receptor Signaling Networks)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Article
Title: Investigating Genetic and Epigenetic Pathogenesis of Hepatitis B virus for Drug Target Identification by Two-sided Time-profile Microarray Data via System Biology and Deep Learning Method
Authors: Bor-Sen Chen, etc.

Article
Title: Protective effects of recombinant human soluble thrombomodulin on lipopolysaccharide-induced acute kidney injury
Authors: Yuji Nozaki, etc.

Title: Synergistic Activation of Toll-Like Receptors by Complementary Antigens as a Facilitator of Autoimmune Disease and Mediator of Sex Hormone-Associated Susceptibility: Review, Theory and Novel Predictions
Author: Robert Root-Bernstein

Review
Title: Immunoregulatory Receptor Signaling Networks in regulating immune reactivity in drug hypersensitivity
Authors: Chun-Bing Chen, etc.

Title: Toll-like receptor 2 expression on myeloid dendritic cells correlates with endometriosis stage and clinical manifestations
Authors: Małgorzata Sobstyl, Ewelina Grywalska, Izabela Korona-Głowniak, Paulina Niedźwiedzka-Rystwej, Anna Sobstyl and Jan Kotarski

Review
Title: The role of TLR on the immune response: PAMPs in OMV vaccines
Authors: Francesca Micoli, etc.

Title: Immunoregulatory Property of Inflammation-Assocociated Lung Diseases
Authors: Tatsuya Nagano, etc.

Title: A fish leukocyte immune-type receptor uses a novel intracytoplasmic tail networking mechanism to cross-inhibit ITAM-dependent phagocytic responses
Authors: Chenjie Fei, Myron A. Zwozdesky, and James L. Stafford

Title: The role of charge in binding of Nε-carboxymethyl lysine modified β-lactoglobulin to receptors for advanced glycation end products
Authors: Gosia Teodorowicz, etc.

Title: The Signalling Network of Macrophage Receptors, VEGFR-MERTK-PD-L1, in the Immunomodulation
Authors: Ko-Tung Chang, etc.

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