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Pathophysiological Mechanisms of Leukocyte Activation and Recruitment

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 19344

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Special Issue Editors

Dr. Giulia Germena

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Guest Editor

1. Laboratory Animal Science Unit, Leibnitz-Institut für Primatenforschung, Deutsches Primatenzentrum GmbH, Kellnerweg 4, 37077 Göttingen, Germany
2. DZHK (German Centre for Cardiovascular Research), Partner Site Göttingen, 37075 Göttingen, Germany
Interests: neutrophil activation; M1 and M2 macrophages; exosomes; sterile inflammation; diabetes; cardiovascular diseases

Dr. Anika Cappenberg

E-Mail Website
Co-Guest Editor

Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, 48149 Munich, Germany
Interests: leukocyte recruitment, inflammation, integrin activation

Special Issue Information

Dear Colleagues,

Inflammation is the protective mechanism of the organism against injurious factors. The major event regulating inflammatory responses is the punctual and localized recruitment of leukocytes. Multiple cellular and regulatory mechanisms have been described playing a role during the multi-step cascade leading to leukocyte recruitment from the bloodstream to the site of inflammation. Deregulations of these molecular mechanisms, causing either an overactivation or a downregulation of leukocyte activation, generate an uncontrolled inflammatory response, a typical feature of multiple pathological conditions, such as, but not limited to, diabetes, arthritis, cancer, and cardiovascular diseases. The analysis of the molecular mechanisms regulating leukocyte activation has highlighted the pivotal role of multiple pathways (integrin activation, cytoskeletal remodeling, NET formations, etc.). In addition, the exploration of the interactions between leukocytes and the vessel wall endothelium has emphasized the importance of this critical interface. Direct cellular interactions and/or paracrine communications are fundamental for a proper leukocyte activation and regulated leukocyte recruitment.

In this Special Issue, we would like to highlight new direct and indirect players involved in the regulation of leukocyte recruitment in pathophysiological conditions and to present advanced approaches to modulate detrimental leukocyte behaviors associated with pathological processes.

I warmly welcome submissions, including original papers and reviews, on this widely discussed topic.

Dr. Giulia Germena
Dr. Anika Cappenberg
Guest Editors

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Keywords

leukocyte recruitment
integrins
inflammation
cytoskeletal remodeling
endothelial cells
macrophage polarization
immunomodulation
paracrine signals
exosomes
cell-cell interaction

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Published Papers (10 papers)

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Research

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20 pages, 6034 KiB

Open AccessArticle

The Effects of IL-23/IL-18-Polarized Neutrophils on Renal Ischemia–Reperfusion Injury and Allogeneic-Skin-Graft Rejection in Mice

by Changhong Wu, Jinglin Xu, Zhaoqi Zhang, Dong Wei, Yanan Xu and Yong Zhao

Biomedicines 2023, 11(12), 3148; https://doi.org/10.3390/biomedicines11123148 - 26 Nov 2023

Cited by 1 | Viewed by 1048

Abstract

Neutrophils display heterogeneity and plasticity with different subgroups and immune-regulatory functions under various surrounding conditions. Neutrophils induced by IL-23/IL-18 (referred to N(IL-23+IL-18) neutrophils) have a unique gene-expression profile, with highly expressing IL-17, MHC-II, and costimulatory molecules. The adoptive transfer of N(IL-23+IL-18) neutrophils significantly increased the pathogenesis in a renal ischemia–reperfusion injury mouse model. N(IL-23+IL-18) neutrophils directly and efficiently induced allogeneic T cell proliferation in vitro. N(IL-23+IL-18) neutrophils enhanced the syngeneic T cell response to allogeneic antigens in mixed-lymphocyte reaction assays. The adoptive transfer of the donor or host N(IL-23+IL-18) neutrophils significantly enhanced the antidonor antibody production in an allogeneic-skin-transplanted mouse model, accompanied by increased Tfh cells in the spleens. Therefore, the neutrophil subset induced by IL-23/IL-18 promotes tissue injury and antidonor humoral response in the allogeneic transplantation mouse model. Full article

(This article belongs to the Special Issue Pathophysiological Mechanisms of Leukocyte Activation and Recruitment)

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23 pages, 4039 KiB

Open AccessArticle

Dysfunctions of Neutrophils in the Peripheral Blood of Children with Cystic Fibrosis

by Ganimeta Bakalović, Dejan Bokonjić, Dušan Mihajlović, Miodrag Čolić, Vanja Mališ, Marija Drakul, Sergej Tomić, Ivan Jojić, Sara Rakočević, Darinka Popović, Ljiljana Kozić, Miloš Vasiljević, Marina Bekić, Srđan Mašić and Olivera Ljuboja

Biomedicines 2023, 11(6), 1725; https://doi.org/10.3390/biomedicines11061725 - 15 Jun 2023

Cited by 1 | Viewed by 1702

Abstract

Dysfunction of neutrophils in patients with cystic fibrosis (CF) is best characterized in bronchoalveolar lavage (BAL), whereas peripheral blood neutrophils are less examined, and the results are contradictory, especially in younger populations. Therefore, this work aimed to study functional and phenotypic changes in circulating neutrophils in children with CF. The study included 19 CF children (5–17 years) and 14 corresponding age-matched healthy children. Isolated neutrophils were cultured either alone or with different stimuli. Several functions were studied: apoptosis, NET-osis, phagocytosis, and production of reactive oxygen species (ROS), neutrophil elastase (NE), and 11 cytokines. In addition, the expression of 20 molecules involved in different functions of neutrophils was evaluated by using flow cytometry. CF neutrophils showed reduced apoptosis and lower production of NE and IL-18 compared to the healthy controls, whereas IL-8 was augmented. All of these functions were further potentiated after neutrophil stimulation, which included higher ROS production and the up-regulation of CD11b and IL-10 expression. NET-osis was higher only when neutrophils from moderate–severe CF were treated with Pseudomonas aeruginosa, and the process correlated with forced expiratory volume in the first second (FEV1). Phagocytosis was not significantly changed. In conclusion, circulating neutrophils from children with CF showed fewer impaired changes in phenotype than in function. Functional abnormalities, which were already present at the baseline levels in neutrophils, depended on the type of stimuli that mimicked different activation states of these cells at the site of infection. Full article

(This article belongs to the Special Issue Pathophysiological Mechanisms of Leukocyte Activation and Recruitment)

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22 pages, 3898 KiB

Open AccessArticle

S100A8/S100A9 Integrates F-Actin and Microtubule Dynamics to Prevent Uncontrolled Extravasation of Leukocytes

by Marc Wolf, Robiya Joseph, Judith Austermann, Chiara Scharrnbeck-Davis, Sven Hermann, Johannes Roth and Thomas Vogl

Biomedicines 2023, 11(3), 835; https://doi.org/10.3390/biomedicines11030835 - 9 Mar 2023

Cited by 4 | Viewed by 2078

Abstract

Immune reactions are characterized by the rapid immigration of phagocytes into sites of inflammation. Meticulous regulation of these migratory processes is crucial for preventing uncontrolled and harmful phagocyte extravasation. S100A8/S100A9 is the major calcium-binding protein complex expressed in phagocytes. After release, this complex acts as a proinflammatory alarmin in the extracellular space, but the intracellular functions of these highly abundant proteins are less clear. Results of this study reveal an important role of S100A8/S100A9 in coordinated cytoskeleton rearrangement during migration. We found that S100A8/S100A9 was able to cross-link F-actin and microtubules in a calcium- and phosphorylation-dependent manner. Cells deficient in S100A8/S100A9 showed abnormalities in cell adhesion and motility. Missing cytoskeletal interactions of S100A8/S100A9 caused differences in the surface expression and activation of β1-integrins as well as in the regulation of Src/Syk kinase family members. Loss of S100A8/S100A9 led to dysregulated integrin-mediated adhesion and migration, resulting in an overall higher dynamic activity of non-activated S100A8/S100A9-deficient phagocytes. Our data suggest that intracellular S100A8/S100A9 is part of a novel regulatory mechanism that ensures the precise control necessary to facilitate the change between the quiescent and activated state of phagocytes. Full article

(This article belongs to the Special Issue Pathophysiological Mechanisms of Leukocyte Activation and Recruitment)

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17 pages, 2640 KiB

Open AccessArticle

Bacterial Outer Membrane Vesicles Promote Lung Inflammatory Responses and Macrophage Activation via Multi-Signaling Pathways

by Sunhyo Ryu, Kareemah Ni, Chenghao Wang, Ayyanar Sivanantham, Jonathan M. Carnino, Hong-Long Ji and Yang Jin

Biomedicines 2023, 11(2), 568; https://doi.org/10.3390/biomedicines11020568 - 15 Feb 2023

Cited by 5 | Viewed by 2118

Abstract

Emerging evidence suggests that Gram-negative bacteria release bacterial outer membrane vesicles (OMVs) and that these play an important role in the pathogenesis of bacterial infection-mediated inflammatory responses and organ damage. Despite the fact that scattered reports have shown that OMVs released from Gram-negative bacteria may function via the TLR2/4-signaling pathway or induce pyroptosis in macrophages, our study reveals a more complex role of OMVs in the development of inflammatory lung responses and macrophage pro-inflammatory activation. We first confirmed that various types of Gram-negative bacteria release similar OMVs which prompt pro-inflammatory activation in both bone marrow-derived macrophages and lung alveolar macrophages. We further demonstrated that mice treated with OMVs via intratracheal instillation developed significant inflammatory lung responses. Using mouse inflammation and autoimmune arrays, we identified multiple altered cytokine/chemokines in both bone marrow-derived macrophages and alveolar macrophages, suggesting that OMVs have a broader spectrum of function compared to LPS. Using TLR4 knock-out cells, we found that OMVs exert more robust effects on activating macrophages compared to LPS. We next examined multiple signaling pathways, including not only cell surface antigens, but also intracellular receptors. Our results confirmed that bacterial OMVs trigger both surface protein-mediated signaling and intracellular signaling pathways, such as the S100-A8 protein-mediated pathway. In summary, our studies confirm that bacterial OMVs strongly induced macrophage pro-inflammatory activation and inflammatory lung responses via multi-signaling pathways. Bacterial OMVs should be viewed as a repertoire of pathogen-associated molecular patterns (PAMPs), exerting more robust effects than Gram-negative bacteria-derived LPS. Full article

(This article belongs to the Special Issue Pathophysiological Mechanisms of Leukocyte Activation and Recruitment)

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20 pages, 4727 KiB

Open AccessArticle

Paralytic Impact of Centrifugation on Human Neutrophils

by Tobias Hundhammer, Michael Gruber and Sigrid Wittmann

Biomedicines 2022, 10(11), 2896; https://doi.org/10.3390/biomedicines10112896 - 11 Nov 2022

Cited by 5 | Viewed by 2344

Abstract

Centrifugation is a common step in most of the popular protocols for the isolation of neutrophils from whole blood. Inconsistent results from previous studies on neutrophils may originate from an underestimation of the centrifugation effect, as in consequence impaired, not native cells, being investigated. We hypothesize, that centrifugation significantly impairs major neutrophil functions. However, there is no data yet whether the application of g-force itself or the product of g-force and duration of centrifugation (=“g-time”) defines the impact on neutrophils. Neutrophils were isolated from whole blood via centrifugation with different g-times and subsequently analyzed via live cell imaging for migration, as well as via flow cytometry for oxidative burst and surface antigen expression. Chemotactic migration was significantly reduced with increasing g-time. Oxidative burst decreased likewise the higher the g-time applied. Expression of CD11b was no longer upregulated in response to an n-formylmethionine-leucyl-phenylalanine (fMLP) stimulus in neutrophils having experienced high g-time during the isolation process. We conclude that centrifugation “paralyzes” neutrophils in the form of a significant decrease in functionality. Future investigations on neutrophil granulocytes should reduce the g-time load as far as possible. Full article

(This article belongs to the Special Issue Pathophysiological Mechanisms of Leukocyte Activation and Recruitment)

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Review

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40 pages, 4324 KiB

Open AccessReview

Inflammation in Prostate Cancer: Exploring the Promising Role of Phenolic Compounds as an Innovative Therapeutic Approach

by Raquel Fernandes, Cátia Costa, Rúben Fernandes and Ana Novo Barros

Biomedicines 2023, 11(12), 3140; https://doi.org/10.3390/biomedicines11123140 - 24 Nov 2023

Cited by 2 | Viewed by 2037

Abstract

Prostate cancer (PCa) remains a significant global health concern, being a major cause of cancer morbidity and mortality worldwide. Furthermore, profound understanding of the disease is needed. Prostate inflammation caused by external or genetic factors is a central player in prostate carcinogenesis. However, the mechanisms underlying inflammation-driven PCa remain poorly understood. This review dissects the diagnosis methods for PCa and the pathophysiological mechanisms underlying the disease, clarifying the dynamic interplay between inflammation and leukocytes in promoting tumour development and spread. It provides updates on recent advances in elucidating and treating prostate carcinogenesis, and opens new insights for the use of bioactive compounds in PCa. Polyphenols, with their noteworthy antioxidant and anti-inflammatory properties, along with their synergistic potential when combined with conventional treatments, offer promising prospects for innovative therapeutic strategies. Evidence from the use of polyphenols and polyphenol-based nanoparticles in PCa revealed their positive effects in controlling tumour growth, proliferation, and metastasis. By consolidating the diverse features of PCa research, this review aims to contribute to increased understanding of the disease and stimulate further research into the role of polyphenols and polyphenol-based nanoparticles in its management. Full article

(This article belongs to the Special Issue Pathophysiological Mechanisms of Leukocyte Activation and Recruitment)

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14 pages, 2252 KiB

Open AccessReview

SKAP2—A Molecule at the Crossroads for Integrin Signalling and Immune Cell Migration and Function

by Marijn Wilmink and Marianne Rebecca Spalinger

Biomedicines 2023, 11(10), 2788; https://doi.org/10.3390/biomedicines11102788 - 14 Oct 2023

Cited by 3 | Viewed by 1442

Abstract

Src-kinase associated protein 2 (SKAP2) is an intracellular scaffolding protein that is broadly expressed in immune cells and is involved in various downstream signalling pathways, including, but not limited to, integrin signalling. SKAP2 has a wide range of binding partners and fine-tunes the rearrangement of the cytoskeleton, thereby regulating cell migration and immune cell function. Mutations in SKAP2 have been associated with several inflammatory disorders such as Type 1 Diabetes and Crohn’s disease. Rodent studies showed that SKAP2 deficient immune cells have diminished pathogen clearance due to impaired ROS production and/or phagocytosis. However, there is currently no in-depth understanding of the functioning of SKAP2. Nevertheless, this review summarises the existing knowledge with a focus of its role in signalling cascades involved in cell migration, tissue infiltration and immune cell function. Full article

(This article belongs to the Special Issue Pathophysiological Mechanisms of Leukocyte Activation and Recruitment)

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15 pages, 1561 KiB

Open AccessReview

Emerging Insights into Molecular Mechanisms of Inflammation in Myelodysplastic Syndromes

by Veronica Vallelonga, Francesco Gandolfi, Francesca Ficara, Matteo Giovanni Della Porta and Serena Ghisletti

Biomedicines 2023, 11(10), 2613; https://doi.org/10.3390/biomedicines11102613 - 23 Sep 2023

Cited by 3 | Viewed by 1723

Abstract

Inflammation impacts human hematopoiesis across physiologic and pathologic conditions, as signals derived from the bone marrow microenvironment, such as pro-inflammatory cytokines and chemokines, have been shown to alter hematopoietic stem cell (HSCs) homeostasis. Dysregulated inflammation can skew HSC fate-related decisions, leading to aberrant hematopoiesis and potentially contributing to the pathogenesis of hematological disorders such as myelodysplastic syndromes (MDS). Recently, emerging studies have used single-cell sequencing and muti-omic approaches to investigate HSC cellular heterogeneity and gene expression in normal hematopoiesis as well as in myeloid malignancies. This review summarizes recent reports mechanistically dissecting the role of inflammatory signaling and innate immune response activation due to MDS progression. Furthermore, we highlight the growing importance of using multi-omic techniques, such as single-cell profiling and deconvolution methods, to unravel MDSs’ heterogeneity. These approaches have provided valuable insights into the patterns of clonal evolution that drive MDS progression and have elucidated the impact of inflammation on the composition of the bone marrow immune microenvironment in MDS. Full article

(This article belongs to the Special Issue Pathophysiological Mechanisms of Leukocyte Activation and Recruitment)

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15 pages, 3313 KiB

Open AccessReview

A History and Atlas of the Human CD4⁺ T Helper Cell

by Jacqueline M. Crater, Daniel C. Dunn, Douglas F. Nixon and Robert L. Furler O’Brien

Biomedicines 2023, 11(10), 2608; https://doi.org/10.3390/biomedicines11102608 - 23 Sep 2023

Viewed by 1819

Abstract

CD4⁺ T cells have orchestrated and regulated immunity since the introduction of jawed vertebrates, yet our understanding of CD4⁺ T cell evolution, development, and cellular physiology has only begun to be unearthed in the past few decades. Discoveries of genetic diseases that ablate this cellular population have provided insight into their critical functions while transcriptomics, proteomics, and high-resolution microscopy have recently revealed new insights into CD4⁺ T cell anatomy and physiology. This article compiles historical, microscopic, and multi-omics data that can be used as a reference atlas and index to dissect cellular physiology within these influential cells and further understand pathologies like HIV infection that inflict human CD4⁺ T cells. Full article

(This article belongs to the Special Issue Pathophysiological Mechanisms of Leukocyte Activation and Recruitment)

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16 pages, 2420 KiB

Open AccessReview

Role of Macrophage lncRNAs in Mediating Inflammatory Processes in Atherosclerosis and Sepsis

by Hyeung-Seob Shin, Jae-Joon Shin, Jeongkwang Park, Imene Arab, Kyoungho Suk and Won-Ha Lee

Biomedicines 2023, 11(7), 1905; https://doi.org/10.3390/biomedicines11071905 - 5 Jul 2023

Cited by 1 | Viewed by 1699

Abstract

Long noncoding RNAs (lncRNAs) are molecules >200 bases in length without protein-coding functions implicated in signal transduction and gene expression regulation via interaction with proteins or RNAs, exhibiting various functions. The expression of lncRNAs has been detected in many cell types, including macrophages, a type of immune cell involved in acute and chronic inflammation, removal of dead or damaged cells, and tissue repair. Increasing evidence indicates that lncRNAs play essential roles in macrophage functions and disease development. Additionally, many animal studies have reported that blockage or modulation of lncRNA functions alleviates disease severity or morbidity rate. The present review summarizes the current knowledge regarding lncRNAs expressed in macrophages, focusing on their molecular targets and the biological processes regulated by them during the development of inflammatory diseases such as atherosclerosis and sepsis. Possible application of this information to lncRNA-targeting therapy is also discussed. The studies regarding macrophage lncRNAs described in this review can help provide valuable information for developing treatments for various pathological conditions involving macrophages. Full article

(This article belongs to the Special Issue Pathophysiological Mechanisms of Leukocyte Activation and Recruitment)

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