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Editorial

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9 pages, 994 KiB

Open AccessEditorial

LL-37, a Multi-Faceted Amphipathic Peptide Involved in NETosis

by Marko Radic and Sylviane Muller

Cells 2022, 11(15), 2463; https://doi.org/10.3390/cells11152463 - 08 Aug 2022

Cited by 7 | Viewed by 2500

Abstract

Innate immunity responds to infections and inflammatory stimuli through a carefully choreographed set of interactions between cells, stimuli and their specific receptors. Of particular importance are endogenous peptides, which assume roles as defensins or alarmins, growth factors or wound repair inducers. LL-37, a [...] Read more.

Innate immunity responds to infections and inflammatory stimuli through a carefully choreographed set of interactions between cells, stimuli and their specific receptors. Of particular importance are endogenous peptides, which assume roles as defensins or alarmins, growth factors or wound repair inducers. LL-37, a proteolytic fragment of cathelicidin, fulfills the roles of a defensin by inserting into the membranes of bacterial pathogens, functions as alarmin in stimulating chemotaxis of innate immune cells, and alters the structure and efficacy of various cytokines. Here, we draw attention to the direct effect of LL-37 on neutrophils and the release of extracellular traps (NETs), as NETs have been established as mediators of immune defense against pathogens but also as important contributors to chronic disease and tissue pathogenesis. We propose a specific structural basis for LL-37 function, in part by highlighting the structural flexibility of LL-37 and its ability to adapt to distinct microenvironments and interacting counterparts. Full article

(This article belongs to the Special Issue NETs in Infectious and Inflammatory Diseases)

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Research

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14 pages, 3009 KiB

Open AccessArticle

S100A8/A9 Is a Marker for the Release of Neutrophil Extracellular Traps and Induces Neutrophil Activation

by Evelien G. G. Sprenkeler, Judith Zandstra, Nadine D. van Kleef, Ines Goetschalckx, Bibian Verstegen, Cathelijn E. M. Aarts, Hans Janssen, Anton T. J. Tool, Gerard van Mierlo, Robin van Bruggen, Ilse Jongerius and Taco W. Kuijpers

Cells 2022, 11(2), 236; https://doi.org/10.3390/cells11020236 - 11 Jan 2022

Cited by 45 | Viewed by 5395

Abstract

Neutrophils are the most abundant innate immune cells in the circulation and they are the first cells recruited to sites of infection or inflammation. Almost half of the intracellular protein content in neutrophils consists of S100A8 and S100A9, though there has been controversy [...] Read more.

Neutrophils are the most abundant innate immune cells in the circulation and they are the first cells recruited to sites of infection or inflammation. Almost half of the intracellular protein content in neutrophils consists of S100A8 and S100A9, though there has been controversy about their actual localization. Once released extracellularly, these proteins are thought to act as damage-associated molecular patterns (DAMPs), though their mechanism of action is not well understood. These S100 proteins mainly form heterodimers (S100A8/A9, also known as calprotectin) and this heterocomplex is recognized as a useful biomarker for several inflammatory diseases. We observed that S100A8/A9 is highly present in the cytoplasmic fraction of neutrophils and is not part of the granule content. Furthermore, we found that S100A8/A9 was not released in parallel with granular content but upon the formation of neutrophil extracellular traps (NETs). Accordingly, neutrophils of patients with chronic granulomatous disease, who are deficient in phorbol 12-myristate 13-acetate (PMA)-induced NETosis, did not release S100A8/A9 upon PMA stimulation. Moreover, we purified S100A8/A9 from the cytoplasmic fraction of neutrophils and found that S100A8/A9 could induce neutrophil activation, including adhesion and CD11b upregulation, indicating that this DAMP might amplify neutrophil activation. Full article

(This article belongs to the Special Issue NETs in Infectious and Inflammatory Diseases)

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28 pages, 6580 KiB

Open AccessArticle

Proteinous Components of Neutrophil Extracellular Traps Are Arrested by the Cell Wall Proteins of Candida albicans during Fungal Infection, and Can Be Used in the Host Invasion

by Justyna Karkowska-Kuleta, Magdalena Smolarz, Karolina Seweryn-Ozog, Dorota Satala, Marcin Zawrotniak, Ewelina Wronowska, Oliwia Bochenska, Andrzej Kozik, Angela H. Nobbs, Mariusz Gogol and Maria Rapala-Kozik

Cells 2021, 10(10), 2736; https://doi.org/10.3390/cells10102736 - 13 Oct 2021

Cited by 14 | Viewed by 2501

Abstract

One of defense mechanisms of the human immune system to counteract infection by the opportunistic fungal pathogen Candida albicans is the recruitment of neutrophils to the site of invasion, and the subsequent production of neutrophil extracellular traps (NETs) that efficiently capture and kill [...] Read more.

One of defense mechanisms of the human immune system to counteract infection by the opportunistic fungal pathogen Candida albicans is the recruitment of neutrophils to the site of invasion, and the subsequent production of neutrophil extracellular traps (NETs) that efficiently capture and kill the invader cells. In the current study, we demonstrate that within these structures composed of chromatin and proteins, the latter play a pivotal role in the entrapment of the fungal pathogen. The proteinous components of NETs, such as the granular enzymes elastase, myeloperoxidase and lactotransferrin, as well as histones and cathelicidin-derived peptide LL-37, are involved in contact with the surface of C. albicans cells. The fungal partners in these interactions are a typical adhesin of the agglutinin-like sequence protein family Als3, and several atypical surface-exposed proteins of cytoplasmic origin, including enolase, triosephosphate isomerase and phosphoglycerate mutase. Importantly, the adhesion of both the elastase itself and the mixture of proteins originating from NETs on the C. albicans cell surface considerably increased the pathogen potency of human epithelial cell destruction compared with fungal cells without human proteins attached. Such an implementation of adsorbed NET-derived proteins by invading C. albicans cells might alter the effectiveness of the fungal pathogen entrapment and affect the further host colonization. Full article

(This article belongs to the Special Issue NETs in Infectious and Inflammatory Diseases)

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16 pages, 2105 KiB

Open AccessArticle

An Autophagy Modulator Peptide Prevents Lung Function Decrease and Corrects Established Inflammation in Murine Models of Airway Allergy

by François Daubeuf, Nicolas Schall, Nathalie Petit-Demoulière, Nelly Frossard and Sylviane Muller

Cells 2021, 10(9), 2468; https://doi.org/10.3390/cells10092468 - 18 Sep 2021

Cited by 12 | Viewed by 2560

Abstract

The involvement of autophagy and its dysfunction in asthma is still poorly documented. By using a murine model of chronic house dust mite (HDM)-induced airway inflammation, we tested the expression of several autophagy markers in the lung and spleen of asthma-like animals. Compared [...] Read more.

The involvement of autophagy and its dysfunction in asthma is still poorly documented. By using a murine model of chronic house dust mite (HDM)-induced airway inflammation, we tested the expression of several autophagy markers in the lung and spleen of asthma-like animals. Compared to control mice, in HDM-sensitized and challenged mice, the expression of sequestosome-1/p62, a multifunctional adaptor protein that plays an important role in the autophagy machinery, was raised in the splenocytes. In contrast, its expression was decreased in the neutrophils recovered from the bronchoalveolar fluid, indicating that autophagy was independently regulated in these two compartments. In a strategy of drug repositioning, we treated allergen-sensitized mice with the therapeutic peptide P140 known to target chaperone-mediated autophagy. A single intravenous administration of P140 in these mice resulted in a significant reduction in airway resistance and elastance, and a reduction in the number of neutrophils and eosinophils present in the bronchoalveolar fluid. It corrected the autophagic alteration without showing any suppressive effect in the production of IgG1 and IgE. Collectively, these findings show that autophagy processes are altered in allergic airway inflammation. This cellular pathway may represent a potential therapeutic target for treating selected patients with asthma. Full article

(This article belongs to the Special Issue NETs in Infectious and Inflammatory Diseases)

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27 pages, 7506 KiB

Open AccessArticle

Scrutinizing Mechanisms of the ‘Obesity Paradox in Sepsis’: Obesity Is Accompanied by Diminished Formation of Neutrophil Extracellular Traps (NETs) Due to Restricted Neutrophil–Platelet Interactions

by Iwona Cichon, Weronika Ortmann, Michal Santocki, Malgorzata Opydo-Chanek and Elzbieta Kolaczkowska

Cells 2021, 10(2), 384; https://doi.org/10.3390/cells10020384 - 12 Feb 2021

Cited by 18 | Viewed by 3969

Abstract

Systemic inflammation is a detrimental condition associated with high mortality. However, obese individuals seem to have higher chances of surviving sepsis. To elucidate what immunological differences exist between obese and lean individuals we studied the course of endotoxemia in mice fed high-fat diet [...] Read more.

Systemic inflammation is a detrimental condition associated with high mortality. However, obese individuals seem to have higher chances of surviving sepsis. To elucidate what immunological differences exist between obese and lean individuals we studied the course of endotoxemia in mice fed high-fat diet (HFD) and ob/ob animals. Intravital microscopy revealed that neutrophil extracellular trap (NET) formation in liver vasculature is negligible in obese mice in sharp contrast to their lean counterparts (ND). Unlike in lean individuals, neutrophil influx is not driven by leptin or interleukin 33 (IL-33), nor occurs via a chemokine receptor CXCR2. In obese mice less platelets interact with neutrophils forming less aggregates. Platelets transfer from ND to HFD mice partially restores NET formation, and even further so upon P-selectin blockage on them. The study reveals that in obesity the overexaggerated inflammation and NET formation are limited during sepsis due to dysfunctional platelets suggesting their targeting as a therapeutic tool in systemic inflammation. Full article

(This article belongs to the Special Issue NETs in Infectious and Inflammatory Diseases)

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Review

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21 pages, 1471 KiB

Open AccessReview

Neutrophil Extracellular Traps Affecting Cardiovascular Health in Infectious and Inflammatory Diseases

by Manovriti Thakur, Bryce Evans, Marc Schindewolf, Iris Baumgartner and Yvonne Döring

Cells 2021, 10(7), 1689; https://doi.org/10.3390/cells10071689 - 04 Jul 2021

Cited by 7 | Viewed by 3886

Abstract

Neutrophil extracellular traps (NETs) are web-like structures of decondensed extracellular chromatin fibers and neutrophil granule proteins released by neutrophils. NETs participate in host immune defense by entrapping pathogens. They are pro-inflammatory in function, and they act as an initiator of vascular coagulopathies by [...] Read more.

Neutrophil extracellular traps (NETs) are web-like structures of decondensed extracellular chromatin fibers and neutrophil granule proteins released by neutrophils. NETs participate in host immune defense by entrapping pathogens. They are pro-inflammatory in function, and they act as an initiator of vascular coagulopathies by providing a platform for the attachment of various coagulatory proteins. NETs are diverse in their ability to alter physiological and pathological processes including infection and inflammation. In this review, we will summarize recent findings on the role of NETs in bacterial/viral infections associated with vascular inflammation, thrombosis, atherosclerosis and autoimmune disorders. Understanding the complex role of NETs in bridging infection and chronic inflammation as well as discussing important questions related to their contribution to pathologies outlined above may pave the way for future research on therapeutic targeting of NETs applicable to specific infections and inflammatory disorders. Full article

(This article belongs to the Special Issue NETs in Infectious and Inflammatory Diseases)

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24 pages, 5239 KiB

Open AccessReview

To Trap a Pathogen: Neutrophil Extracellular Traps and Their Role in Mucosal Epithelial and Skin Diseases

by Carolina Domínguez-Díaz, Gael Urait Varela-Trinidad, Germán Muñoz-Sánchez, Karla Solórzano-Castanedo, Karina Elizabeth Avila-Arrezola, Liliana Iñiguez-Gutiérrez, Vidal Delgado-Rizo and Mary Fafutis-Morris

Cells 2021, 10(6), 1469; https://doi.org/10.3390/cells10061469 - 11 Jun 2021

Cited by 16 | Viewed by 4190

Abstract

Neutrophils are the most abundant circulating innate immune cells and comprise the first immune defense line, as they are the most rapidly recruited cells at sites of infection or inflammation. Their main microbicidal mechanisms are degranulation, phagocytosis, cytokine secretion and the formation of [...] Read more.

Neutrophils are the most abundant circulating innate immune cells and comprise the first immune defense line, as they are the most rapidly recruited cells at sites of infection or inflammation. Their main microbicidal mechanisms are degranulation, phagocytosis, cytokine secretion and the formation of extracellular traps. Neutrophil extracellular traps (NETs) are a microbicidal mechanism that involves neutrophil death. Since their discovery, in vitro and in vivo neutrophils have been challenged with a range of stimuli capable of inducing or inhibiting NET formation, with the objective to understand its function and regulation in health and disease. These networks composed of DNA and granular components are capable of immobilizing and killing pathogens. They comprise enzymes such as myeloperoxidase, elastase, cathepsin G, acid hydrolases and cationic peptides, all with antimicrobial and antifungal activity. Therefore, the excessive formation of NETs can also lead to tissue damage and promote local and systemic inflammation. Based on this concept, in this review, we focus on the role of NETs in different infectious and inflammatory diseases of the mucosal epithelia and skin. Full article

(This article belongs to the Special Issue NETs in Infectious and Inflammatory Diseases)

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18 pages, 2083 KiB

Open AccessReview

Immunologically Inert Nanostructures as Selective Therapeutic Tools in Inflammatory Diseases

by Laura Talamini, Eiji Matsuura, Luisa De Cola and Sylviane Muller

Cells 2021, 10(3), 707; https://doi.org/10.3390/cells10030707 - 23 Mar 2021

Cited by 4 | Viewed by 3233

Abstract

The current therapies based on immunosuppressant or new biologic drugs often show some limitations in term of efficacy and applicability, mainly because of their inadequate targeting and of unwanted adverse reactions they generate. To overcome these inherent problems, in the last decades, innovative [...] Read more.

The current therapies based on immunosuppressant or new biologic drugs often show some limitations in term of efficacy and applicability, mainly because of their inadequate targeting and of unwanted adverse reactions they generate. To overcome these inherent problems, in the last decades, innovative nanocarriers have been developed to encapsulate active molecules and offer novel promising strategies to efficiently modulate the immune system. This review provides an overview of how it is possible, exploiting the favorable features of nanocarriers, especially with regard to their immunogenicity, to improve the bioavailability of novel drugs that selectively target immune cells in the context of autoimmune disorders and inflammatory diseases. A focus is made on nanoparticles that selectively target neutrophils in inflammatory pathologies. Full article

(This article belongs to the Special Issue NETs in Infectious and Inflammatory Diseases)

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