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The Role of Toll-Like Receptors (TLRs) in Infection and Inflammation 2.0

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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: 31 July 2024 | Viewed by 14011

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Dr. Ralf Kircheis

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Syntacoll GmbH, Saal an der Donau, 93342 Bayern, Germany
Interests: toll-like receptors; NF-kappaB; COVID-19; cytokines; gene therapy; immune therapy
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Oliver Planz

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Institute of Cell Biology and Immunology, Eberhard Karls University, 72076 Tuebingen, Germany
Interests: immunology of viral infections; host cell targeted antivirals; virus cell interaction
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Toll-like receptors (TLRs) represent a powerful system for the recognition and elimination of pathogen-associated molecular patterns (PAMPs) from bacteria, viruses, and other pathogens as well as damage-associated molecular patterns (DAMPs) released from dying or lytic cells. TLRs are mainly expressed on immune cells but can also be present on some tissue-resident cell populations. Typical PAMPs are cell wall components of bacterial and viral pathogens, conserved proteins, or pathogenic nucleic acids, including viral RNA and DNA.

Activation of TLRs leads to the production of proinflammatory cytokines and type I interferons, which are critical for induction of the host immune response against bacterial, fungal, and viral infections and malaria. However, dysregulation and overstimulation can be detrimental, leading to hyperinflammation, sepsis, and loss of tissue integrity. TLRs are involved in the pathogenesis of acute viral infections, including in the case of COVID-19. Altogether, the activation of TLRs plays a deciding role in both the induction of immunity and the pathophysiological effects associated with excessive activation, indicating TLRs as promising targets for pharmacological intervention and treatment.

Topics of interest include, but are not limited to:

Activation of TLRs and their downstream signaling pathways and correlation with the immunology and pathophysiology of bacterial and viral infectious diseases.
Translational research, pharmacological and medical interventions with TLR activation and signaling, and their use as therapeutic targets for bacterial and viral infectious diseases, including COVID-19.
Clinical or model studies, though only in conjunction with biomolecular experiments.

Dr. Ralf Kircheis
Prof. Dr. Oliver Planz
Guest Editors

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Keywords

toll-like receptors (TLRs)
pathogen-associated molecular patterns (PAMPs)
sepsis
bacterial infections
viral infections
Myd88
TRIF
NF-kappaB
COVID-19
coagulopathies

Published Papers (7 papers)

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Research

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16 pages, 6614 KiB

Open AccessArticle

Regulation of Cathelicidin Antimicrobial Peptide (CAMP) Gene Expression by TNFα and cfDNA in Adipocytes

by Alexandra Höpfinger, Andreas Schmid, Leonie Schweitzer, Marissa Patz, Anja Weber, Andreas Schäffler and Thomas Karrasch

Int. J. Mol. Sci. 2023, 24(21), 15820; https://doi.org/10.3390/ijms242115820 - 31 Oct 2023

Cited by 1 | Viewed by 1947

Abstract

Understanding the complex interactions between metabolism and the immune system (“metaflammation”) is crucial for the identification of key immunomodulatory factors as potential therapeutic targets in obesity and in cardiovascular diseases. Cathelicidin antimicrobial peptide (CAMP) is an important factor of innate immunity and is expressed in adipocytes. CAMP, therefore, might play a role as an adipokine in metaflammation and adipose inflammation. TNFα, cell-free nucleic acids (cfDNA), and toll-like receptor (TLR) 9 are components of the innate immune system and are functionally active in adipose tissue. The aim of the present study was to investigate the impact of TNFα and cfDNA on CAMP expression in adipocytes. Since cfDNA acts as a physiological TLR9 agonist, we additionally investigated TLR9-mediated CAMP regulation in adipocytes and adipose tissue. CAMP gene expression in murine 3T3-L1 and human SGBS adipocytes and in murine and human adipose tissues was quantified by real-time PCR. Adipocyte inflammation was induced in vitro by TNFα and cfDNA stimulation. Serum CAMP concentrations in TLR9 knockout (KO) and in wildtype mice were quantified by ELISA. In primary adipocytes of wildtype and TLR9 KO mice, CAMP gene expression was quantified by real-time PCR. CAMP gene expression was considerably increased in 3T3-L1 and SGBS adipocytes during differentiation. TNFα significantly induced CAMP gene expression in mature adipocytes, which was effectively antagonized by inhibition of PI3K signaling. Cell-free nucleic acids (cfDNA) significantly impaired CAMP gene expression, whereas synthetic agonistic and antagonistic TLR9 ligands had no effect. CAMP and TLR9 gene expression were correlated positively in murine and human subcutaneous but not in intra-abdominal/visceral adipose tissues. Male TLR9 knockout mice exhibited lower systemic CAMP concentrations than wildtype mice. CAMP gene expression levels in primary adipocytes did not significantly differ between wildtype and TLR9 KO mice. These findings suggest a regulatory role of inflammatory mediators, such as TNFα and cfDNA, in adipocytic CAMP expression as a novel putative molecular mechanism in adipose tissue innate immunity. Full article

(This article belongs to the Special Issue The Role of Toll-Like Receptors (TLRs) in Infection and Inflammation 2.0)

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36 pages, 4537 KiB

Open AccessArticle

n-3 Polyunsaturated Fatty Acids Modulate LPS-Induced ARDS and the Lung–Brain Axis of Communication in Wild-Type versus Fat-1 Mice Genetically Modified for Leukotriene B4 Receptor 1 or Chemerin Receptor 23 Knockout

by Jessica Hernandez, Julia Schäffer, Christiane Herden, Fabian Johannes Pflieger, Sylvia Reiche, Svenja Körber, Hiromu Kitagawa, Joelle Welter, Susanne Michels, Carsten Culmsee, Jens Bier, Natascha Sommer, Jing X. Kang, Konstantin Mayer, Matthias Hecker and Christoph Rummel

Int. J. Mol. Sci. 2023, 24(17), 13524; https://doi.org/10.3390/ijms241713524 - 31 Aug 2023

Cited by 1 | Viewed by 1368

Abstract

Specialized pro-resolving mediators (SPMs) and especially Resolvin E1 (RvE1) can actively terminate inflammation and promote healing during lung diseases such as acute respiratory distress syndrome (ARDS). Although ARDS primarily affects the lung, many ARDS patients also develop neurocognitive impairments. To investigate the connection between the lung and brain during ARDS and the therapeutic potential of SPMs and its derivatives, fat-1 mice were crossbred with RvE1 receptor knockout mice. ARDS was induced in these mice by intratracheal application of lipopolysaccharide (LPS, 10 µg). Mice were sacrificed at 0 h, 4 h, 24 h, 72 h, and 120 h post inflammation, and effects on the lung, liver, and brain were assessed by RT-PCR, multiplex, immunohistochemistry, Western blot, and LC-MS/MS. Protein and mRNA analyses of the lung, liver, and hypothalamus revealed LPS-induced lung inflammation increased inflammatory signaling in the hypothalamus despite low signaling in the periphery. Neutrophil recruitment in different brain structures was determined by immunohistochemical staining. Overall, we showed that immune cell trafficking to the brain contributed to immune-to-brain communication during ARDS rather than cytokines. Deficiency in RvE1 receptors and enhanced omega-3 polyunsaturated fatty acid levels (fat-1 mice) affect lung–brain interaction during ARDS by altering profiles of several inflammatory and lipid mediators and glial activity markers. Full article

(This article belongs to the Special Issue The Role of Toll-Like Receptors (TLRs) in Infection and Inflammation 2.0)

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19 pages, 7835 KiB

Open AccessArticle

The Role of Toll-like Receptor-4 in Macrophage Imbalance in Lethal COVID-19 Lung Disease, and Its Correlation with Galectin-3

by Maria Carmela Pedicillo, Ilenia Sara De Stefano, Rosanna Zamparese, Raffaele Barile, Mario Meccariello, Alessio Agostinone, Giuliana Villani, Tommaso Colangelo, Gaetano Serviddio, Tommaso Cassano, Andrea Ronchi, Renato Franco, Paola Pannone, Federica Zito Marino, Francesco Miele, Maurizio Municinò and Giuseppe Pannone

Int. J. Mol. Sci. 2023, 24(17), 13259; https://doi.org/10.3390/ijms241713259 - 26 Aug 2023

Viewed by 1224

Abstract

To the current data, there have been 6,955,141 COVID-19-related deaths worldwide, reported to WHO. Toll-like receptors (TLRs) implicated in bacterial and virus sensing could be a crosstalk between activation of persistent innate-immune inflammation, and macrophage’s sub-population alterations, implicated in cytokine storm, macrophage over-activation syndrome, unresolved Acute Respiratory Disease Syndrome (ARDS), and death. The aim of this study is to demonstrate the association between Toll-like-receptor-4 (TLR-4)-induced inflammation and macrophage imbalance in the lung inflammatory infiltrate of lethal COVID-19 disease. Twenty-five cases of autopsy lung tissues were studied by digital pathology-based immunohistochemistry to evaluate expression levels of TLR-4 (CD 284), pan-macrophage marker CD68 (clone KP1), sub-population marker related to alveolar macrophage Galectin-3 (GAL-3) (clone 9C4), and myeloid derived CD163 (clone MRQ-26), respectively. SARS-CoV-2 viral persistence has been evaluated by in situ hybridation (ISH) method. This study showed TLR-4 up-regulation in a subgroup of patients, increased macrophage infiltration in both Spike-1⁽⁺⁾ and Spike-1⁽⁻⁾ lungs (p < 0.0001), and a macrophage shift with important down-regulation of GAL-3⁽⁺⁾ alveolar macrophages associated with Spike-1 persistence (p < 0.05), in favor of CD163⁽⁺⁾ myeloid derived monocyte-macrophages. Data show that TLR-4 expression induces a persistent activation of the inflammation, with inefficient resolution, and pathological macrophage shift, thus explaining one of the mechanisms of lethal COVID-19. Full article

(This article belongs to the Special Issue The Role of Toll-Like Receptors (TLRs) in Infection and Inflammation 2.0)

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12 pages, 968 KiB

Open AccessCommunication

MYD88 and Proinflammatory Chemokines in Aortic Atheromatosis: Exploring Novel Statin Effects

by Konstantinos S. Mylonas, Michail Peroulis, Dimitrios Schizas and Alkistis Kapelouzou

Int. J. Mol. Sci. 2023, 24(11), 9248; https://doi.org/10.3390/ijms24119248 - 25 May 2023

Cited by 4 | Viewed by 1264

Abstract

Atherosclerosis is driven by a diverse range of cellular and molecular processes. In the present study, we sought to better understand how statins mitigate proatherogenic inflammation. 48 male New Zealand rabbits were divided into eight groups, each including 6 animals. The control groups received normal chow for 90 and 120 days. Three groups underwent a hypercholesterolemic diet (HCD) for 30, 60, and 90 days. Another three groups underwent HCD for 3 months, followed by normal chow for one month, with or without rosuvastatin or fluvastatin. The cytokine and chemokine expressions were assessed in the samples of thoracic and abdominal aorta. Rosuvastatin significantly reduced MYD88, CCL4, CCL20, CCR2, TNF-α, IFN-β, IL-1b, IL-2, IL-4, IL-8, and IL-10, both in the thoracic and abdominal aorta. Fluvastatin also downregulated MYD88, CCR2, IFN-β, IFN-γ, IL-1b, IL-2, IL-4, and IL-10 in both aortic segments. Rosuvastatin curtailed the expression of CCL4, IFN-β, IL-2, IL-4, and IL-10 more effectively than fluvastatin in both types of tissue. MYD88, TNF-α, IL-1b, and IL-8 showed a stronger downregulation with rosuvastatin compared to fluvastatin only in the thoracic aorta. The CCL20 and CCR2 levels reduced more extensively with rosuvastatin treatment only in abdominal aortic tissue. In conclusion, statin therapy can halt proatherogenic inflammation in hyperlipidemic animals. Rosuvastatin may be more effective in downregulating MYD88 in atherosclerotic thoracic aortas. Full article

(This article belongs to the Special Issue The Role of Toll-Like Receptors (TLRs) in Infection and Inflammation 2.0)

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Review

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18 pages, 1736 KiB

Open AccessReview

An Update on Toll-like Receptor 2, Its Function and Dimerization in Pro- and Anti-Inflammatory Processes

by Katrin Colleselli, Anna Stierschneider and Christoph Wiesner

Int. J. Mol. Sci. 2023, 24(15), 12464; https://doi.org/10.3390/ijms241512464 - 05 Aug 2023

Cited by 2 | Viewed by 2486

Abstract

While a certain level of inflammation is critical for humans to survive infection and injury, a prolonged inflammatory response can have fatal consequences. Pattern recognition Toll-like receptors (TLRs) are key players in the initiation of an inflammatory process. TLR2 is one of the most studied pattern recognition receptors (PRRs) and is known to form heterodimers with either TLR1, TLR4, TLR6, and TLR10, allowing it to recognize a wide range of pathogens. Although a large number of studies have been conducted over the past decades, there are still many unanswered questions regarding TLR2 mechanisms in health and disease. In this review, we provide an up-to-date overview of TLR2, including its homo- and heterodimers. Furthermore, we will discuss the pro- and anti-inflammatory properties of TLR2 and recent findings in prominent TLR2-associated infectious and neurodegenerative diseases. Full article

(This article belongs to the Special Issue The Role of Toll-Like Receptors (TLRs) in Infection and Inflammation 2.0)

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20 pages, 1144 KiB

Open AccessReview

Toll-like Receptor Response to Human Immunodeficiency Virus Type 1 or Co-Infection with Hepatitis B or C Virus: An Overview

by Mohammad Enamul Hoque Kayesh, Michinori Kohara and Kyoko Tsukiyama-Kohara

Int. J. Mol. Sci. 2023, 24(11), 9624; https://doi.org/10.3390/ijms24119624 - 01 Jun 2023

Cited by 5 | Viewed by 1770

Abstract

Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors that play important roles in the early detection of pathogen-associated molecular patterns and shaping innate and adaptive immune responses, which may influence the consequences of infection. Similarly to other viral infections, human immunodeficiency virus type 1 (HIV-1) also modulates the host TLR response; therefore, a proper understanding of the response induced by human HIV-1 or co-infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), due to the common mode of transmission of these viruses, is essential for understanding HIV-1 pathogenesis during mono- or co-infection with HBV or HCV, as well as for HIV-1 cure strategies. In this review, we discuss the host TLR response during HIV-1 infection and the innate immune evasion mechanisms adopted by HIV-1 for infection establishment. We also examine changes in the host TLR response during HIV-1 co-infection with HBV or HCV; however, this type of study is extremely scarce. Moreover, we discuss studies investigating TLR agonists as latency-reverting agents and immune stimulators towards new strategies for curing HIV. This understanding will help develop a new strategy for curing HIV-1 mono-infection or co-infection with HBV or HCV. Full article

(This article belongs to the Special Issue The Role of Toll-Like Receptors (TLRs) in Infection and Inflammation 2.0)

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21 pages, 1548 KiB

Open AccessReview

TLRs: Innate Immune Sentries against SARS-CoV-2 Infection

by Stefania Mantovani, Barbara Oliviero, Stefania Varchetta, Alessandra Renieri and Mario U. Mondelli

Int. J. Mol. Sci. 2023, 24(9), 8065; https://doi.org/10.3390/ijms24098065 - 29 Apr 2023

Cited by 9 | Viewed by 3047

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been responsible for a devastating pandemic since March 2020. Toll-like receptors (TLRs), crucial components in the initiation of innate immune responses to different pathogens, trigger the downstream production of pro-inflammatory cytokines, interferons, and other mediators. It has been demonstrated that they contribute to the dysregulated immune response observed in patients with severe COVID-19. TLR2, TLR3, TLR4 and TLR7 have been associated with COVID-19 severity. Here, we review the role of TLRs in the etiology and pathogenesis of COVID-19, including TLR7 and TLR3 rare variants, the L412F polymorphism in TLR3 that negatively regulates anti-SARS-CoV-2 immune responses, the TLR3-related cellular senescence, the interaction of TLR2 and TLR4 with SARS-CoV-2 proteins and implication of TLR2 in NET formation by SARS-CoV-2. The activation of TLRs contributes to viral clearance and disease resolution. However, TLRs may represent a double-edged sword which may elicit dysregulated immune signaling, leading to the production of proinflammatory mediators, resulting in severe disease. TLR-dependent excessive inflammation and TLR-dependent antiviral response may tip the balance towards the former or the latter, altering the equilibrium that drives the severity of disease. Full article

(This article belongs to the Special Issue The Role of Toll-Like Receptors (TLRs) in Infection and Inflammation 2.0)

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