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State-of-Art in Innate Immunity

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (25 July 2022) | Viewed by 35382

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Special Issue Editors

Dr. Silvia Fischer

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Guest Editor

Department of Biochemistry, Medical School, Justus-Liebig-University, 35392 Giessen, Germany
Interests: homeostasis; extracellular nucleic acids; vascular endothelium; inflammation; DAMPs
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Elisabeth Deindl

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Guest Editor

Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
Interests: cardiovascular research; immunology
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

The innate immune system is the first line of defence against pathogens and protects against bacterial and viral infections through the recognition of pathogen-associated molecular patterns (PAMPs), which recruit and activate pathogen recognition receptors (PRRs) resulting in the production of proinflammatory and antiviral cytokines and chemokines. Additionally, PRRs are recognized by damage-associated molecular patterns (DAMPs), which were released by passive or active mechanisms under sterile conditions such as shear stress, ischemic injuries, trauma, or tumors. Once released, DAMPs serve as alarmins by triggering inflammation, dendritic cell maturation, activation of immune cells, and promoting regeneration and remodeling processes. DAMPs involve nuclear or cytosolic proteins such as histones, high mobility group box 1 (HMGB1), adenosine triphosphate, DNA, or RNA and can also be used as biomarkers to indicate and monitor a disease or injury severity. During infectious diseases, DAMPs can even aggravate the inflammatory response, whereby the initial hyperinflammatory phase is counterbalanced by an anti-inflammatory response, which is possibly caused by the production of suppressing/inhibiting inducible DAMPs (SAMPs).

The present issue aims to demonstrate new advances in the mechanisms of DAMP and SAMP release under sterile conditions as well as the consequences of their extracellular innate immune signaling and activities. Furthermore, the usefulness of DAMPs/SAMPs as biomarkers for special diseases and as therapeutic targets to decrease hyperinflammatory processes will be summarized.

Dr. Silvia Fischer
Dr. Elisabeth Deindl
Guest Editors

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Keywords

inflammation
sterile injury
damage-associated molecular pattern
DAMP

Published Papers (11 papers)

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Editorial

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2 pages, 184 KiB

Open AccessEditorial

State of the Art of Innate Immunity—An Overview

by Silvia Fischer and Elisabeth Deindl

Cells 2022, 11(17), 2705; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11172705 - 30 Aug 2022

Cited by 1 | Viewed by 1374

Abstract

The innate immune system is the first line of defense against bacterial and viral infections and sterile inflammation through the recognition of pathogen-associated molecular patterns (PAMPs) as well as danger-associated molecular patterns (DAMPs) by pathogen-recognition receptors (PRRs), and produces proinflammatory and antiviral cytokines [...] Read more.

(This article belongs to the Special Issue State-of-Art in Innate Immunity)

Research

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17 pages, 3859 KiB

Open AccessArticle

Effect of Thrombin on the Metabolism and Function of Murine Macrophages

by Ürün Ukan, Fredy Delgado Lagos, Sebastian Kempf, Stefan Günther, Mauro Siragusa, Beate Fisslthaler and Ingrid Fleming

Cells 2022, 11(10), 1718; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11101718 - 23 May 2022

Cited by 5 | Viewed by 2623

Abstract

Macrophages are plastic and heterogeneous immune cells that adapt pro- or anti-inflammatory phenotypes upon exposure to different stimuli. Even though there has been evidence supporting a crosstalk between coagulation and innate immunity, the way in which protein components of the hemostasis pathway influence macrophages remains unclear. We investigated the effect of thrombin on macrophage polarization. On the basis of gene expression and cytokine secretion, our results suggest that polarization with thrombin induces an anti-inflammatory, M2-like phenotype. In functional studies, thrombin polarization promoted oxLDL phagocytosis by macrophages, and conditioned medium from the same cells increased endothelial cell proliferation. There were, however, clear differences between the classical M2a polarization and the effects of thrombin on gene expression. Finally, the deletion and inactivation of secreted modular Ca²⁺-binding protein 1 (SMOC1) attenuated phagocytosis by thrombin-stimulated macrophages, a phenomenon revered by the addition of recombinant SMOC1. Manipulation of SMOC1 levels also had a pronounced impact on the expression of TGF-β-signaling-related genes. Taken together, our results show that thrombin induces an anti-inflammatory macrophage phenotype with similarities as well as differences to the classical alternatively activated M2 polarization states, highlighting the importance of tissue levels of SMOC1 in modifying thrombin-induced macrophage polarization. Full article

(This article belongs to the Special Issue State-of-Art in Innate Immunity)

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20 pages, 4773 KiB

Open AccessArticle

Depletion of γδ T Cells Leads to Reduced Angiogenesis and Increased Infiltration of Inflammatory M1-like Macrophages in Ischemic Muscle Tissue

by Christoph Arnholdt, Konda Kumaraswami, Philipp Götz, Matthias Kübler, Manuel Lasch and Elisabeth Deindl

Cells 2022, 11(9), 1490; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11091490 - 29 Apr 2022

Cited by 7 | Viewed by 2213

Abstract

γδ T cells, a small subset of T cells in blood, play a substantial role in influencing immunoregulatory and inflammatory processes. The functional impact of γδ T cells on angiogenesis in ischemic muscle tissue has never been reported and is the topic of the present work. Femoral artery ligation (FAL) was used to induce angiogenesis in the lower leg of γδ T cell depleted mice and wildtype and isotype antibody-treated control groups. Gastrocnemius muscle tissue was harvested 3 and 7 days after FAL and assessed using (immuno-)histological analyses. Hematoxylin and Eosin staining showed an increased area of tissue damage in γδ T cell depleted mice 7 days after FAL. Impaired angiogenesis was demonstrated by lower capillary to muscle fiber ratio and decreased number of proliferating endothelial cells (CD31⁺/BrdU⁺). γδ T cell depleted mice showed an increased number of total leukocytes (CD45⁺), neutrophils (MPO⁺) and neutrophil extracellular traps (NETs) (MPO⁺/CitH3⁺), without changes in the neutrophils to NETs ratio. Moreover, the depletion resulted in a higher macrophage count (DAPI/CD68⁺) caused by an increase in inflammatory M1-like macrophages (CD68⁺/MRC1⁻). Altogether, we show that depletion of γδ T cells leads to increased accumulation of leukocytes and M1-like macrophages, along with impaired angiogenesis. Full article

(This article belongs to the Special Issue State-of-Art in Innate Immunity)

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Graphical abstract

18 pages, 3016 KiB

Open AccessArticle

Extracellular Ribosomal RNA Acts Synergistically with Toll-like Receptor 2 Agonists to Promote Inflammation

by Karsten Grote, Marina Nicolai, Uwe Schubert, Bernhard Schieffer, Christian Troidl, Klaus T. Preissner, Stefan Bauer and Silvia Fischer

Cells 2022, 11(9), 1440; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11091440 - 24 Apr 2022

Cited by 3 | Viewed by 1778

Abstract

Self-extracellular RNA (eRNA), which is released under pathological conditions from damaged tissue, has recently been identified as a new alarmin and synergistic agent together with toll-like receptor (TLR)2 ligands to induce proinflammatory activities of immune cells. In this study, a detailed investigation of these interactions is reported. The macrophage cell line J774 A.1 or C57 BL/6 J wild-type mice were treated with 18S rRNA and different TLR2 agonists. Gene and protein expression of tumor necrosis factor (Tnf)-α; interleukin (Il)-1β, Il-6; or monocyte chemoattractant protein (Mcp)-1 were analyzed and furthermore in vitro binding studies to TLR2 were performed. The TLR2/TLR6-agonist Pam₂ CSK₄ (Pam2) together with 18S rRNA significantly increased the mRNA expression of inflammatory genes and the release of TNF-α from macrophages in a TLR2- and nuclear factor kappa B (NF-κB)-dependent manner. The injection of 18S rRNA/Pam2 into mice increased the cytokine levels of TNF-α, IL-6, and MCP-1 in the peritoneal lavage. Mechanistically, 18S rRNA built complexes with Pam2 and thus enhanced the affinity of Pam2 to TLR2. These results indicate that the alarmin eRNA, mainly consisting of rRNA, sensitizes TLR2 to enhance the innate immune response under pathological conditions. Thus, rRNA might serve as a new target for the treatments of bacterial and viral infections. Full article

(This article belongs to the Special Issue State-of-Art in Innate Immunity)

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13 pages, 3019 KiB

Open AccessArticle

The Cellular Innate Immune Response of the Invasive Pest Insect Drosophila suzukii against Pseudomonas entomophila Involves the Release of Extracellular Traps

by Tessa Carrau, Susanne Thümecke, Liliana M. R. Silva, David Perez-Bravo, Ulrich Gärtner, Anja Taubert, Carlos Hermosilla, Andreas Vilcinskas and Kwang-Zin Lee

Cells 2021, 10(12), 3320; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10123320 - 26 Nov 2021

Cited by 7 | Viewed by 2862

Abstract

Drosophila suzukii is a neobiotic invasive pest that causes extensive damage to fruit crops worldwide. The biological control of this species has been unsuccessful thus far, in part because of its robust cellular innate immune system, including the activity of professional phagocytes known as hemocytes and plasmatocytes. The in vitro cultivation of primary hemocytes isolated from D. suzukii third-instar larvae is a valuable tool for the investigation of hemocyte-derived effector mechanisms against pathogens such as wasp parasitoid larvae, bacteria, fungi and viruses. Here, we describe the morphological characteristics of D. suzukii hemocytes and evaluate early innate immune responses, including extracellular traps released against the entomopathogen Pseudomonas entomophila and lipopolysaccharides. We show for the first time that D. suzukii plasmatocytes cast extracellular traps to combat P. entomophila, along with other cell-mediated reactions, such as phagocytosis and the formation of filopodia. Full article

(This article belongs to the Special Issue State-of-Art in Innate Immunity)

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17 pages, 2566 KiB

Open AccessArticle

The Endothelin Receptor Antagonist Macitentan Inhibits Human Cytomegalovirus Infection

by Natalia Landázuri, Jennifer Gorwood, Ylva Terelius, Fredrik Öberg, Koon Chu Yaiw, Afsar Rahbar and Cecilia Söderberg-Nauclér

Cells 2021, 10(11), 3072; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10113072 - 08 Nov 2021

Cited by 2 | Viewed by 2063

Abstract

Human cytomegalovirus (HCMV) infection is an important cause of morbidity and mortality in immunocompromised patients and a major etiological factor for congenital birth defects in newborns. Ganciclovir and its pro-drug valganciclovir are the preferred drugs in use today for prophylaxis and treatment of viremic patients. Due to long treatment times, patients are at risk for developing viral resistance to ganciclovir and to other drugs with a similar mechanism of action. We earlier found that the endothelin receptor B (ETBR) is upregulated during HCMV infection and that it plays an important role in the life cycle of this virus. Here, we tested the hypothesis that ETBR blockade could be used in the treatment of HCMV infection. As HCMV infection is specific to humans, we tested our hypothesis in human cell types that are relevant for HCMV pathogenesis; i.e., endothelial cells, epithelial cells and fibroblasts. We infected these cells with HCMV and treated them with the ETBR specific antagonist BQ788 or ETR antagonists that are approved by the FDA for treatment of pulmonary hypertension; macitentan, its metabolite ACT-132577, bosentan and ambrisentan, and as an anti-viral control, we used ganciclovir or letermovir. At concentrations expected to be relevant in vivo, macitentan, ACT-132577 and BQ788 effectively inhibited productive infection of HCMV. Of importance, macitentan also inhibited productive infection of a ganciclovir-resistant HCMV isolate. Our results suggest that binding or signaling through ETBR is crucial for viral replication, and that selected ETBR blockers inhibit HCMV infection. Full article

(This article belongs to the Special Issue State-of-Art in Innate Immunity)

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14 pages, 1943 KiB

Open AccessArticle

Albumin Might Attenuate Bacteria-Induced Damage on Kupffer Cells for Patients with Chronic Liver Disease

by Hao Lin, Yuhui Fan, Andreas Wieser, Jiang Zhang, Ivonne Regel, Hanno Nieß, Julia Mayerle, Alexander L. Gerbes and Christian J. Steib

Cells 2021, 10(9), 2298; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10092298 - 03 Sep 2021

Cited by 5 | Viewed by 2255

Abstract

Chronic liver diseases (CLDs) are complex diseases that cause long-term inflammation and infection, which in turn accelerate their development. The usage of albumin in patients with CLDs has been debated for years. Human serum albumin (HSA) plays a key role in immunomodulation during the process of CLDs. The correlation between albumin and C-reactive protein (CRP) in CLD patients was analyzed by linear regression with the Pearson statistic. The damage of THP-1 and primary cells was evaluated by measuring the lactate dehydrogenase (LDH) in the supernatant. Immunofluorescence staining was performed to determine underlying pathways in Kupffer cells (KCs). Albumin negatively correlated with infection in patients with CLDs. In vitro experiments with THP-1 cells and KCs showed that albumin reduced LDH release after stimulation with bacterial products, while no differences in hepatic stellate cells (HSCs) and sinusoidal endothelial cells (SECs) were detected. Moreover, immunofluorescence staining revealed an increase of p-ERK and p-NF-kB p65 density after albumin treatment of KCs stimulated by bacterial products. In conclusion, albumin could assist CLD patients in alleviating inflammation caused by bacterial products and might be beneficial to patients with CLDs by securing KCs from bacteria-induced damage, providing a compelling rationale for albumin therapy in patients with CLDs. Full article

(This article belongs to the Special Issue State-of-Art in Innate Immunity)

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Review

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20 pages, 1154 KiB

Open AccessReview

It’s All in the PAN: Crosstalk, Plasticity, Redundancies, Switches, and Interconnectedness Encompassed by PANoptosis Underlying the Totality of Cell Death-Associated Biological Effects

by Jessica M. Gullett, Rebecca E. Tweedell and Thirumala-Devi Kanneganti

Cells 2022, 11(9), 1495; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11091495 - 29 Apr 2022

Cited by 38 | Viewed by 7862

Abstract

The innate immune system provides the first line of defense against cellular perturbations. Innate immune activation elicits inflammatory programmed cell death in response to microbial infections or alterations in cellular homeostasis. Among the most well-characterized programmed cell death pathways are pyroptosis, apoptosis, and necroptosis. While these pathways have historically been defined as segregated and independent processes, mounting evidence shows significant crosstalk among them. These molecular interactions have been described as ‘crosstalk’, ‘plasticity’, ‘redundancies’, ‘molecular switches’, and more. Here, we discuss the key components of cell death pathways and note several examples of crosstalk. We then explain how the diverse descriptions of crosstalk throughout the literature can be interpreted through the lens of an integrated inflammatory cell death concept, PANoptosis. The totality of biological effects in PANoptosis cannot be individually accounted for by pyroptosis, apoptosis, or necroptosis alone. We also discuss PANoptosomes, which are multifaceted macromolecular complexes that regulate PANoptosis. We consider the evidence for PANoptosis, which has been mechanistically characterized during influenza A virus, herpes simplex virus 1, Francisella novicida, and Yersinia infections, as well as in response to altered cellular homeostasis, in inflammatory diseases, and in cancers. We further discuss the role of IRF1 as an upstream regulator of PANoptosis and conclude by reexamining historical studies which lend credence to the PANoptosis concept. Cell death has been shown to play a critical role in infections, inflammatory diseases, neurodegenerative diseases, cancers, and more; therefore, having a holistic understanding of cell death is important for identifying new therapeutic strategies. Full article

(This article belongs to the Special Issue State-of-Art in Innate Immunity)

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25 pages, 2031 KiB

Open AccessReview

Proteostasis Perturbations and Their Roles in Causing Sterile Inflammation and Autoinflammatory Diseases

by Jonas Johannes Papendorf, Elke Krüger and Frédéric Ebstein

Cells 2022, 11(9), 1422; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11091422 - 22 Apr 2022

Cited by 7 | Viewed by 2530

Abstract

Proteostasis, a portmanteau of the words protein and homeostasis, refers to the ability of eukaryotic cells to maintain a stable proteome by acting on protein synthesis, quality control and/or degradation. Over the last two decades, an increasing number of disorders caused by proteostasis perturbations have been identified. Depending on their molecular etiology, such diseases may be classified into ribosomopathies, proteinopathies and proteasomopathies. Strikingly, most—if not all—of these syndromes exhibit an autoinflammatory component, implying a direct cause-and-effect relationship between proteostasis disruption and the initiation of innate immune responses. In this review, we provide a comprehensive overview of the molecular pathogenesis of these disorders and summarize current knowledge of the various mechanisms by which impaired proteostasis promotes autoinflammation. We particularly focus our discussion on the notion of how cells sense and integrate proteostasis perturbations as danger signals in the context of autoinflammatory diseases to provide insights into the complex and multiple facets of sterile inflammation. Full article

(This article belongs to the Special Issue State-of-Art in Innate Immunity)

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17 pages, 4149 KiB

Open AccessReview

Post-Translational Modification of HMGB1 Disulfide Bonds in Stimulating and Inhibiting Inflammation

by Ulf Andersson, Kevin J. Tracey and Huan Yang

Cells 2021, 10(12), 3323; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10123323 - 26 Nov 2021

Cited by 33 | Viewed by 4570

Abstract

High mobility group box 1 protein (HMGB1), a highly conserved nuclear DNA-binding protein, is a “damage-associated molecular pattern” molecule (DAMP) implicated in both stimulating and inhibiting innate immunity. As reviewed here, HMGB1 is an oxidation-reduction sensitive DAMP bearing three cysteines, and the post-translational modification of these residues establishes its proinflammatory and anti-inflammatory activities by binding to different extracellular cell surface receptors. The redox-sensitive signaling mechanisms of HMGB1 also occupy an important niche in innate immunity because HMGB1 may carry other DAMPs and pathogen-associated molecular pattern molecules (PAMPs). HMGB1 with DAMP/PAMP cofactors bind to the receptor for advanced glycation end products (RAGE) which internalizes the HMGB1 complexes by endocytosis for incorporation in lysosomal compartments. Intra-lysosomal HMGB1 disrupts lysosomal membranes thereby releasing the HMGB1-transported molecules to stimulate cytosolic sensors that mediate inflammation. This HMGB1-DAMP/PAMP cofactor pathway slowed the development of HMGB1-binding antagonists for diagnostic or therapeutic use. However, recent discoveries that HMGB1 released from neurons mediates inflammation via the TLR4 receptor system, and that cancer cells express fully oxidized HMGB1 as an immunosuppressive mechanism, offer new paths to targeting HMGB1 for inflammation, pain, and cancer. Full article

(This article belongs to the Special Issue State-of-Art in Innate Immunity)

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10 pages, 1235 KiB

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Crosstalk between Interleukin-1β and Type I Interferons Signaling in Autoinflammatory Diseases

by Philippe Georgel

Cells 2021, 10(5), 1134; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10051134 - 08 May 2021

Cited by 6 | Viewed by 2454

Abstract

Interleukin-1β (IL-1β) and type I interferons (IFNs) are major cytokines involved in autoinflammatory/autoimmune diseases. Separately, the overproduction of each of these cytokines is well described and constitutes the hallmark of inflammasomopathies and interferonopathies, respectively. While their interaction and the crosstalk between their downstream signaling pathways has been mostly investigated in the frame of infectious diseases, little information on their interconnection is still available in the context of autoinflammation promoted by sterile triggers. In this review, we will examine the respective roles of IL-1β and type I IFNs in autoinflammatory/rheumatic diseases and analyze their potential connections in the pathophysiology of some of these diseases, which could reveal novel therapeutic opportunities. Full article

(This article belongs to the Special Issue State-of-Art in Innate Immunity)

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