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Immunoregulatory Receptor Signaling Networks

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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 May 2020) | Viewed by 69560

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Dr. James L. Stafford

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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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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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Immunoregulatory Receptor Signaling Networks 2.0 in International Journal of Molecular Sciences (2 articles)

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15 pages, 2028 KiB

Open AccessArticle

Aryl Hydrocarbon Receptor Signaling Is Functional in Immune Cells of Rainbow Trout (Oncorhynchus mykiss)

by Jun-Young Song, Ayako Casanova-Nakayama, Anja-Maria Möller, Shin-Ichi Kitamura, Kei Nakayama and Helmut Segner

Int. J. Mol. Sci. 2020, 21(17), 6323; https://doi.org/10.3390/ijms21176323 - 31 Aug 2020

Cited by 15 | Viewed by 3569

Abstract

The arylhydrocarbon receptor (AhR) is an important signaling pathway in the immune system of mammals. In addition to its physiological functions, the receptor mediates the immunotoxic actions of a diverse range of environmental contaminants that bind to and activate the AhR, including planar halogenated aromatic hydrocarbons (PHAHs or dioxin-like compounds) and polynuclear aromatic hydrocarbons (PAHs). AhR-binding xenobiotics are immunotoxic not only to mammals but to teleost fish as well. To date, however, it is unknown if the AhR pathway is active in the immune system of fish and thus may act as molecular initiating event in the immunotoxicity of AhR-binding xenobiotics to fish. The present study aims to examine the presence of functional AhR signaling in immune cells of rainbow trout (Oncorhynchus mykiss). Focus is given to the toxicologically relevant AhR2 clade. By means of RT-qPCR and in situ hybdridization, we show that immune cells of rainbow trout express ahr 2α and ahr 2β mRNA; this applies for immune cells isolated from the head kidney and from the peripheral blood. Furthermore, we show that in vivo as well as in vitro exposure to the AhR ligand, benzo(a)pyrene (BaP), causes upregulation of the AhR-regulated gene, cytochrome p4501a, in rainbow trout immune cells, and that this induction is inhibited by co-treatment with an AhR antagonist. Taken together, these findings provide evidence that functional AhR signaling exists in the immune cells of the teleost species, rainbow trout. Full article

(This article belongs to the Special Issue Immunoregulatory Receptor Signaling Networks)

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30 pages, 14287 KiB

Open AccessArticle

A Fish Leukocyte Immune-Type Receptor Uses a Novel Intracytoplasmic Tail Networking Mechanism to Cross-Inhibit the Phagocytic Response

by Chenjie Fei, Myron A. Zwozdesky and James L. Stafford

Int. J. Mol. Sci. 2020, 21(14), 5146; https://doi.org/10.3390/ijms21145146 - 21 Jul 2020

Cited by 6 | Viewed by 2590

Abstract

Channel catfish (Ictalurus punctatus) leukocyte immune-type receptors (IpLITRs) are a family of immunoregulatory proteins shown to regulate several innate immune cell effector responses, including phagocytosis. The precise mechanisms of IpLITR-mediated regulation of the phagocytic process are not entirely understood, but we have previously shown that different IpLITR-types use classical as well as novel pathways for controlling immune cell-mediated target engulfment. To date, all functional assessments of IpLITR-mediated regulatory actions have focused on the independent characterization of select IpLITR-types in transfected cells. As members of the immunoglobulin superfamily, many IpLITRs share similar extracellular Ig-like domains, thus it is possible that various IpLITR actions are influenced by cross-talk mechanisms between different IpLITR-types; analogous to the paired innate receptor paradigm in mammals. Here, we describe in detail the co-expression of different IpLITR-types in the human embryonic AD293 cell line and examination of their receptor cross-talk mechanisms during the regulation of the phagocytic response using imaging flow cytometry, confocal microscopy, and immunoprecipitation protocols. Overall, our data provides interesting new insights into the integrated control of phagocytosis via the antagonistic networking of independent IpLITR-types that requires the selective recruitment of inhibitory signaling molecules for the initiation and sustained cross-inhibition of phagocytosis. Full article

(This article belongs to the Special Issue Immunoregulatory Receptor Signaling Networks)

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16 pages, 2955 KiB

Open AccessArticle

Binding of CML-Modified as Well as Heat-Glycated β-lactoglobulin to Receptors for AGEs Is Determined by Charge and Hydrophobicity

by Hannah E. Zenker, Malgorzata Teodorowicz, Arifa Ewaz, R.J. Joost van Neerven, Huub F.J. Savelkoul, Nicolette W. De Jong, Harry J. Wichers and Kasper A. Hettinga

Int. J. Mol. Sci. 2020, 21(12), 4567; https://doi.org/10.3390/ijms21124567 - 26 Jun 2020

Cited by 13 | Viewed by 3217

Abstract

Intake of dietary advanced glycation end products (AGEs) is associated with inflammation-related health problems. Nε-carboxymethyl lysine (CML) is one of the best characterised AGEs in processed food. AGEs have been described as ligands for receptors present on antigen presenting cells. However, changes in protein secondary and tertiary structure also induce binding to AGE receptors. We aimed to discriminate the role of different protein modifications in binding to AGE receptors. Therefore, β-lactoglobulin was chemically modified with glyoxylic acid to produce CML and compared to β-lactoglobulin glycated with lactose. Secondary structure was monitored with circular dichroism, while hydrophobicity and formation of β-sheet structures was measured with ANS-assay and ThT-assay, respectively. Aggregation was monitored using native-PAGE. Binding to sRAGE, CD36, and galectin-3 was measured using inhibition ELISA. Even though no changes in secondary structure were observed in all tested samples, binding to AGE receptors increased with CML concentration of CML-modified β-lactoglobulin. The negative charge of CML was a crucial determinant for the binding of protein bound CML, while binding of glycated BLG was determined by increasing hydrophobicity. This shows that sRAGE, galectin-3, and CD36 bind to protein bound CML and points out the role of negatively charged AGEs in binding to AGE receptors. Full article

(This article belongs to the Special Issue Immunoregulatory Receptor Signaling Networks)

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16 pages, 5296 KiB

Open AccessArticle

Pulmonary Involvement in a Mouse Model of Sjögren’s Syndrome Induced by STING Activation

by Joanna Papinska, Harini Bagavant, Grzegorz B. Gmyrek and Umesh S. Deshmukh

Int. J. Mol. Sci. 2020, 21(12), 4512; https://doi.org/10.3390/ijms21124512 - 25 Jun 2020

Cited by 14 | Viewed by 3343

Abstract

Sjögren’s Syndrome (SS), a chronic autoimmune disorder affecting multiple organ systems, is characterized by an elevated type I interferon (IFN) response. Activation of Stimulator of Interferon Genes (STING) protein induces type I IFN and in mice, several features of SS, including anti-nuclear antibodies, sialadenitis, and salivary gland dysfunction. Since lung involvement occurs in one-fifth of SS patients, we investigated whether systemic activation of STING also leads to lung inflammation. Lungs from female C57BL/6 mice injected with the STING agonist 5, 6-Dimethylxanthenone-4-acetic acid (DMXAA), were evaluated for acute and chronic inflammatory responses. Within 4h of DMXAA injection, the expression of Ifnb1, Il6, Tnf, Ifng, and Mx1 was significantly upregulated. At 1 and 2 months post-treatment, lungs showed lymphocytic infiltration in the peri-bronchial regions. The lungs from DMXAA treated mice showed an increased expression of multiple chemokines and an increase in lymphatic endothelial cells. Despite STING expression in bronchial epithelium and cells lining the alveolar wall, bone marrow chimeras between STING knockout and wild type mice showed that STING expression in hematopoietic cells was critical for lung inflammation. Our results suggest that activation of the STING pathway might be involved in SS patients with concomitant salivary gland and lung disease. Full article

(This article belongs to the Special Issue Immunoregulatory Receptor Signaling Networks)

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12 pages, 2112 KiB

Open AccessArticle

Nasal Epithelial Cells Activated with Alternaria and House Dust Mite Induce Not Only Th2 but Also Th1 Immune Responses

by Seung-Heon Shin, Mi-Kyung Ye, Dong-Won Lee, Mi-Hyun Chae and Ba-Da Han

Int. J. Mol. Sci. 2020, 21(8), 2693; https://doi.org/10.3390/ijms21082693 - 13 Apr 2020

Cited by 10 | Viewed by 3108

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 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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14 pages, 3324 KiB

Open AccessArticle

Protective Effects of Recombinant Human Soluble Thrombomodulin on Lipopolysaccharide-Induced Acute Kidney Injury

by Yuji Nozaki, Jinhai Ri, Kenji Sakai, Kaoru Niki, Masanori Funauchi and Itaru Matsumura

Int. J. Mol. Sci. 2020, 21(7), 2519; https://doi.org/10.3390/ijms21072519 - 5 Apr 2020

Cited by 12 | Viewed by 3321

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 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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18 pages, 4640 KiB

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

by Ha Thi Thu Do, Bich Phuong Bui, Seongrak Sim, Jae-Kyung Jung, Heesoon Lee and Jungsook Cho

Int. J. Mol. Sci. 2020, 21(7), 2319; https://doi.org/10.3390/ijms21072319 - 27 Mar 2020

Cited by 35 | Viewed by 6099

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, 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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13 pages, 902 KiB

Open AccessReview

FcεRI Signaling in the Modulation of Allergic Response: Role of Mast Cell-Derived Exosomes

by Mario Lecce, Rosa Molfetta, Nadia Domenica Milito, Angela Santoni and Rossella Paolini

Int. J. Mol. Sci. 2020, 21(15), 5464; https://doi.org/10.3390/ijms21155464 - 30 Jul 2020

Cited by 24 | Viewed by 3944

Abstract

Mast cells (MCs) are immune cells that act as environment resident sentinels playing a crucial role in Th2-mediated immune responses, including allergic reactions. Distinguishing features of MCs are the presence of numerous cytoplasmic granules that encapsulate a wide array of preformed bio-active molecules and the constitutive expression of the high affinity receptor of IgE (FcεRI). Upon FcεRI engagement by means of IgE and multivalent antigens, aggregated receptors trigger biochemical pathways that ultimately lead to the release of granule-stored and newly synthesized pro-inflammatory mediators. Additionally, MCs are also able to release exosomes either constitutively or upon stimulation. Exosomes are nanosized vesicles of endocytic origin endowed with important immunoregulatory properties, and represent an additional way of intercellular communication. Interestingly, exosomes generated upon FcεRI engagement contain co-stimulatory and adhesion molecules, lipid mediators, and MC-specific proteases, as well as receptor subunits together with IgE and antigens. These findings support the notion that FcεRI signaling plays an important role in influencing the composition and functions of exosomes derived by MCs depending on their activation status. Full article

(This article belongs to the Special Issue Immunoregulatory Receptor Signaling Networks)

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16 pages, 1962 KiB

Open AccessReview

Nuclear Receptors, Ligands and the Mammalian B Cell

by Bart G. Jones, Rhiannon R. Penkert, Sherri L. Surman, Robert E. Sealy and Julia L. Hurwitz

Int. J. Mol. Sci. 2020, 21(14), 4997; https://doi.org/10.3390/ijms21144997 - 15 Jul 2020

Cited by 4 | Viewed by 2627

Abstract

Questions concerning the influences of nuclear receptors and their ligands on mammalian B cells are vast in number. Here, we briefly review the effects of nuclear receptor ligands, including estrogen and vitamins, on immunoglobulin production and protection from infectious diseases. We describe nuclear receptor interactions with the B cell genome and the potential mechanisms of gene regulation. Attention to the nuclear receptor/ligand regulation of B cell function may help optimize B cell responses, improve pathogen clearance, and prevent damaging responses toward inert- and self-antigens. Full article

(This article belongs to the Special Issue Immunoregulatory Receptor Signaling Networks)

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34 pages, 4307 KiB

Open AccessReview

Synergistic Activation of Toll-Like and NOD Receptors by Complementary Antigens as Facilitators of Autoimmune Disease: Review, Model and Novel Predictions

by Robert Root-Bernstein

Int. J. Mol. Sci. 2020, 21(13), 4645; https://doi.org/10.3390/ijms21134645 - 30 Jun 2020

Cited by 18 | Viewed by 4470

Abstract

Persistent activation of toll-like receptors (TLR) and nucleotide-binding oligomerization domain-containing proteins (NOD) in the innate immune system is one necessary driver of autoimmune disease (AD), but its mechanism remains obscure. This study compares and contrasts TLR and NOD activation profiles for four AD (autoimmune myocarditis, myasthenia gravis, multiple sclerosis and rheumatoid arthritis) and their animal models. The failure of current AD theories to explain the disparate TLR/NOD profiles in AD is reviewed and a novel model is presented that explains innate immune support of persistent chronic inflammation in terms of unique combinations of complementary AD-specific antigens stimulating synergistic TLRs and/or NODs. The potential explanatory power of the model is explored through testable, novel predictions concerning TLR- and NOD-related AD animal models and therapies. Full article

(This article belongs to the Special Issue Immunoregulatory Receptor Signaling Networks)

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17 pages, 1132 KiB

Open AccessReview

Cannabis, the Endocannabinoid System and Immunity—the Journey from the Bedside to the Bench and Back

by Osnat Almogi-Hazan and Reuven Or

Int. J. Mol. Sci. 2020, 21(12), 4448; https://doi.org/10.3390/ijms21124448 - 23 Jun 2020

Cited by 85 | Viewed by 19423

Abstract

The Cannabis plant contains numerous components, including cannabinoids and other active molecules. The phyto-cannabinoid activity is mediated by the endocannabinoid system. Cannabinoids affect the nervous system and play significant roles in the regulation of the immune system. While Cannabis is not yet registered as a drug, the potential of cannabinoid-based medicines for the treatment of various conditions has led many countries to authorize their clinical use. However, the data from basic and medical research dedicated to medical Cannabis is currently limited. A variety of pathological conditions involve dysregulation of the immune system. For example, in cancer, immune surveillance and cancer immuno-editing result in immune tolerance. On the other hand, in autoimmune diseases increased immune activity causes tissue damage. Immuno-modulating therapies can regulate the immune system and therefore the immune-regulatory properties of cannabinoids, suggest their use in the therapy of immune related disorders. In this contemporary review, we discuss the roles of the endocannabinoid system in immunity and explore the emerging data about the effects of cannabinoids on the immune response in different pathologies. In addition, we discuss the complexities of using cannabinoid-based treatments in each of these conditions. Full article

(This article belongs to the Special Issue Immunoregulatory Receptor Signaling Networks)

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19 pages, 1079 KiB

Open AccessReview

OMV Vaccines and the Role of TLR Agonists in Immune Response

by Francesca Mancini, Omar Rossi, Francesca Necchi and Francesca Micoli

Int. J. Mol. Sci. 2020, 21(12), 4416; https://doi.org/10.3390/ijms21124416 - 21 Jun 2020

Cited by 102 | Viewed by 9004

Abstract

Outer Membrane Vesicles (OMVs) are bacterial nanoparticles that are spontaneously released during growth both in vitro and in vivo by Gram-negative bacteria. They are spherical, bilayered membrane nanostructures that contain many components found within the external surface of the parent bacterium. Naturally, OMVs serve the bacteria as a mechanism to deliver DNA, RNA, proteins, and toxins, as well as to promote biofilm formation and remodel the outer membrane during growth. On the other hand, as OMVs possess the optimal size to be uptaken by immune cells, and present a range of surface-exposed antigens in native conformation and Toll-like receptor (TLR) activating components, they represent an attractive and powerful vaccine platform able to induce both humoral and cell-mediated immune responses. This work reviews the TLR-agonists expressed on OMVs and their capability to trigger individual TLRs expressed on different cell types of the immune system, and then focuses on their impact on the immune responses elicited by OMVs compared to traditional vaccines. Full article

(This article belongs to the Special Issue Immunoregulatory Receptor Signaling Networks)

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16 pages, 2363 KiB

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Immunoregulatory Property of C-Type Lectin-Like Receptors in Fibrosing Interstitial Lung Diseases

by Wiwin Is Effendi, Tatsuya Nagano, Helmia Hasan and Resti Yudhawati

Int. J. Mol. Sci. 2020, 21(10), 3665; https://doi.org/10.3390/ijms21103665 - 22 May 2020

Cited by 8 | Viewed by 4130

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) 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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