Research

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15 pages, 1698 KiB

Open AccessFeature PaperArticle

Role of S100A8/A9 in Platelet–Neutrophil Complex Formation during Acute Inflammation

by Julian Revenstorff, Nadine Ludwig, Annika Hilger, Sina Mersmann, Martin Lehmann, Julia Chiara Grenzheuser, Marina Kardell, Julia Bone, Niklas Martin Kötting, Nina Christine Marx, Johannes Roth, Thomas Vogl and Jan Rossaint

Cells 2022, 11(23), 3944; https://doi.org/10.3390/cells11233944 - 06 Dec 2022

Cited by 5 | Viewed by 2896

Abstract

Acute respiratory distress syndrome (ARDS) due to pulmonary infections is associated with high morbidity and mortality. Upon inflammation, the alarmin S100A8/A9 is released and stimulates neutrophil recruitment mainly via binding to Toll-like receptor 4 (TLR4). TLR4 is also expressed on platelets, which modulate [...] Read more.

Acute respiratory distress syndrome (ARDS) due to pulmonary infections is associated with high morbidity and mortality. Upon inflammation, the alarmin S100A8/A9 is released and stimulates neutrophil recruitment mainly via binding to Toll-like receptor 4 (TLR4). TLR4 is also expressed on platelets, which modulate the immune response through direct interaction with leukocytes. In a murine model of Klebsiella pneumoniae-induced pulmonary inflammation, global S100A9 deficiency resulted in diminished neutrophil recruitment into the lung alveoli and neutrophil accumulation in the intravascular space, indicating an impaired neutrophil migration. A lack of TLR4 on platelets resulted in reduced neutrophil counts in the whole lung, emphasising the impact of TLR4-mediated platelet activity on neutrophil behaviour. Flow cytometry-based analysis indicated elevated numbers of platelet–neutrophil complexes in the blood of S100A9^−/− mice. Intravital microscopy of the murine cremaster muscle confirmed these findings and further indicated a significant increase in neutrophil–platelet complex formation in S100A9^−/− mice, which was reversed by administration of the S100A8/A9 tetramer. An in vitro bilayer assay simulated the murine alveolar capillary barrier during inflammation and validated significant differences in transmigration behaviour between wild-type and S100A9^−/− neutrophils. This study demonstrates the role of S100A8/A9 during platelet–neutrophil interactions and neutrophil recruitment during pulmonary inflammation. Full article

(This article belongs to the Special Issue The Maladaptive Immune Response in Innate and Adaptive Immunity during Systemic Inflammation)

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17 pages, 6603 KiB

Open AccessArticle

Modulation of Neutrophil Activity by Soluble Complement Cleavage Products—An In-Depth Analysis

by Lisa Wohlgemuth, Alexander Elias Paul Stratmann, Frederik Münnich, Stefan Bernhard, Bertram Dietrich Thomaß, Finn Münnich, Adam Omar Khalaf Mohamed, Marco Mannes, Christoph Quirin Schmidt, Kristina Nilsson Ekdahl, Bo Nilsson, Michael Fauler, Karl Josef Föhr, Markus Huber-Lang and David Alexander Christian Messerer

Cells 2022, 11(20), 3297; https://doi.org/10.3390/cells11203297 - 20 Oct 2022

Cited by 2 | Viewed by 2719

Abstract

The cellular and fluid phase-innate immune responses of many diseases predominantly involve activated neutrophil granulocytes and complement factors. However, a comparative systematic analysis of the early impact of key soluble complement cleavage products, including anaphylatoxins, on neutrophil granulocyte function is lacking. Neutrophil activity [...] Read more.

The cellular and fluid phase-innate immune responses of many diseases predominantly involve activated neutrophil granulocytes and complement factors. However, a comparative systematic analysis of the early impact of key soluble complement cleavage products, including anaphylatoxins, on neutrophil granulocyte function is lacking. Neutrophil activity was monitored by flow cytometry regarding cellular (electro-)physiology, cellular activity, and changes in the surface expression of activation markers. The study revealed no major effects induced by C3a or C4a on neutrophil functions. By contrast, exposure to C5a or C5a des-Arg stimulated neutrophil activity as reflected in changes in membrane potential, intracellular pH, glucose uptake, and cellular size. Similarly, C5a and C5a des-Arg but no other monitored complement cleavage product enhanced phagocytosis and reactive oxygen species generation. C5a and C5a des-Arg also altered the neutrophil surface expression of several complement receptors and neutrophil activation markers, including C5aR1, CD62L, CD10, and CD11b, among others. In addition, a detailed characterization of the C5a-induced effects was performed with a time resolution of seconds. The multiparametric response of neutrophils was further analyzed by a principal component analysis, revealing CD11b, CD10, and CD16 to be key surrogates of the C5a-induced effects. Overall, we provide a comprehensive insight into the very early interactions of neutrophil granulocytes with activated complement split products and the resulting neutrophil activity. The results provide a basis for a better and, importantly, time-resolved and multiparametric understanding of neutrophil-related (patho-)physiologies. Full article

(This article belongs to the Special Issue The Maladaptive Immune Response in Innate and Adaptive Immunity during Systemic Inflammation)

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12 pages, 2407 KiB

Open AccessArticle

Analysis of Leukocyte Recruitment in Continuous Veno-Venous Hemofiltration with Regional Citrate vs. Systemic Heparin Anticoagulation

by Andreas Margraf, Chang Liu, Mira Küllmar, Melanie Meersch, Jan Rossaint and Alexander Zarbock

Cells 2022, 11(11), 1815; https://doi.org/10.3390/cells11111815 - 01 Jun 2022

Cited by 1 | Viewed by 1715

Abstract

Acute kidney injury (AKI) is a frequent complication in critically ill patients. Supportive treatment of AKI patients is based on renal-replacement therapy, including continuous veno-venous hemofiltration (CVVH). To limit clotting events on extracorporeal surfaces, anticoagulants are administered, including systemic heparin and local citrate. [...] Read more.

Acute kidney injury (AKI) is a frequent complication in critically ill patients. Supportive treatment of AKI patients is based on renal-replacement therapy, including continuous veno-venous hemofiltration (CVVH). To limit clotting events on extracorporeal surfaces, anticoagulants are administered, including systemic heparin and local citrate. The differential and comparative effects of these anticoagulants on leukocyte function in acute kidney injury patients are, so far, insufficiently understood. In this bio-add-on-study, AKI patients were randomized as part of a parallel-group trial to either systemic heparin or regional citrate anticoagulation. Patient samples were collected upon inclusion, prior to CVVH initiation at day 0, day 1, day 3 and day 5, following CVVH initiation, and one day after cessation of CVVH, then immediately analyzed. Flow cytometric assessment of surface-receptor molecules was conducted. Whole-blood-perfused human microfluidic chambers were used for the analysis of neutrophil rolling and adhesion. Acute kidney injury was associated with significant changes in the surface expression of CD182 and CD16 throughout CVVH treatment, independent of the anticoagulation regime. AKI furthermore abrogated selectin-induced slow leukocyte rolling and diminished chemokine-induced leukocyte arrest. Subgroup analyses of citrate vs. heparin treatment showed no significant differences between groups, independent of the duration of CVVH treatment. CD182 and CD16 expression remained low in both groups throughout CVVH therapy. These data confirm that AKI impairs selectin-mediated leukocyte slow rolling and chemokine-induced leukocyte arrest in vitro. Systemic heparin or local citrate anticoagulation have no differential effect on the leukocyte recruitment steps examined in this study. Full article

(This article belongs to the Special Issue The Maladaptive Immune Response in Innate and Adaptive Immunity during Systemic Inflammation)

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Review

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31 pages, 1910 KiB

Open AccessReview

Virus Infection and Systemic Inflammation: Lessons Learnt from COVID-19 and Beyond

by Aileen Faist, Josua Janowski, Sriram Kumar, Saskia Hinse, Duygu Merve Çalışkan, Julius Lange, Stephan Ludwig and Linda Brunotte

Cells 2022, 11(14), 2198; https://doi.org/10.3390/cells11142198 - 14 Jul 2022

Cited by 8 | Viewed by 3504

Abstract

Respiratory infections with newly emerging zoonotic viruses such as SARS-CoV-2, the etiological agent of COVID-19, often lead to the perturbation of the human innate and adaptive immune responses causing severe disease with high mortality. The responsible mechanisms are commonly virus-specific and often include [...] Read more.

Respiratory infections with newly emerging zoonotic viruses such as SARS-CoV-2, the etiological agent of COVID-19, often lead to the perturbation of the human innate and adaptive immune responses causing severe disease with high mortality. The responsible mechanisms are commonly virus-specific and often include either over-activated or delayed local interferon responses, which facilitate efficient viral replication in the primary target organ, systemic viral spread, and rapid onset of organ-specific and harmful inflammatory responses. Despite the distinct replication strategies, human infections with SARS-CoV-2 and highly pathogenic avian influenza viruses demonstrate remarkable similarities and differences regarding the mechanisms of immune induction, disease dynamics, as well as the long-term sequelae, which will be discussed in this review. In addition, we will highlight some important lessons about the effectiveness of antiviral and immunomodulatory therapeutic strategies that this pandemic has taught us. Full article

(This article belongs to the Special Issue The Maladaptive Immune Response in Innate and Adaptive Immunity during Systemic Inflammation)

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23 pages, 1941 KiB

Open AccessEditor’s ChoiceReview

The Good and the Bad: Monocytes’ and Macrophages’ Diverse Functions in Inflammation

by Judith Austermann, Johannes Roth and Katarzyna Barczyk-Kahlert

Cells 2022, 11(12), 1979; https://doi.org/10.3390/cells11121979 - 20 Jun 2022

Cited by 40 | Viewed by 7002

Abstract

Monocytes and macrophages are central players of the innate immune response and play a pivotal role in the regulation of inflammation. Thereby, they actively participate in all phases of the immune response, from initiating inflammation and triggering the adaptive immune response, through to [...] Read more.

Monocytes and macrophages are central players of the innate immune response and play a pivotal role in the regulation of inflammation. Thereby, they actively participate in all phases of the immune response, from initiating inflammation and triggering the adaptive immune response, through to the clearance of cell debris and resolution of inflammation. In this review, we described the mechanisms of monocyte and macrophage adaptation to rapidly changing microenvironmental conditions and discussed different forms of macrophage polarization depending on the environmental cues or pathophysiological condition. Therefore, special focus was placed on the tight regulation of the pro- and anti-inflammatory immune response, and the diverse functions of S100A8/S100A9 proteins and the scavenger receptor CD163 were highlighted, respectively. We paid special attention to the function of pro- and anti-inflammatory macrophages under pathological conditions. Full article

(This article belongs to the Special Issue The Maladaptive Immune Response in Innate and Adaptive Immunity during Systemic Inflammation)

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20 pages, 2000 KiB

Open AccessEditor’s ChoiceReview

Platelets at the Crossroads of Pro-Inflammatory and Resolution Pathways during Inflammation

by Nadine Ludwig, Annika Hilger, Alexander Zarbock and Jan Rossaint

Cells 2022, 11(12), 1957; https://doi.org/10.3390/cells11121957 - 17 Jun 2022

Cited by 22 | Viewed by 5895

Abstract

Platelets are among the most abundant cells in the mammalian circulation. Classical platelet functions in hemostasis and wound healing have been intensively explored and are generally accepted. During the past decades, the research focus broadened towards their participation in immune-modulatory events, including pro-inflammatory [...] Read more.

Platelets are among the most abundant cells in the mammalian circulation. Classical platelet functions in hemostasis and wound healing have been intensively explored and are generally accepted. During the past decades, the research focus broadened towards their participation in immune-modulatory events, including pro-inflammatory and, more recently, inflammatory resolution processes. Platelets are equipped with a variety of abilities enabling active participation in immunological processes. Toll-like receptors mediate the recognition of pathogens, while the release of granule contents and microvesicles promotes direct pathogen defense and an interaction with leukocytes. Platelets communicate and physically interact with neutrophils, monocytes and a subset of lymphocytes via soluble mediators and surface adhesion receptors. This interaction promotes leukocyte recruitment, migration and extravasation, as well as the initiation of effector functions, such as the release of extracellular traps by neutrophils. Platelet-derived prostaglandin E2, C-type lectin-like receptor 2 and transforming growth factor β modulate inflammatory resolution processes by promoting the synthesis of pro-resolving mediators while reducing pro-inflammatory ones. Furthermore, platelets promote the differentiation of CD4⁺ T cells in T helper and regulatory T cells, which affects macrophage polarization. These abilities make platelets key players in inflammatory diseases such as pneumonia and the acute respiratory distress syndrome, including the pandemic coronavirus disease 2019. This review focuses on recent findings in platelet-mediated immunity during acute inflammation. Full article

(This article belongs to the Special Issue The Maladaptive Immune Response in Innate and Adaptive Immunity during Systemic Inflammation)

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21 pages, 1316 KiB

Open AccessReview

Regulation and Dysregulation of Endothelial Permeability during Systemic Inflammation

by Katharina E. M. Hellenthal, Laura Brabenec and Nana-Maria Wagner

Cells 2022, 11(12), 1935; https://doi.org/10.3390/cells11121935 - 15 Jun 2022

Cited by 41 | Viewed by 6678

Abstract

Systemic inflammation can be triggered by infection, surgery, trauma or burns. During systemic inflammation, an overshooting immune response induces tissue damage resulting in organ dysfunction and mortality. Endothelial cells make up the inner lining of all blood vessels and are critically involved in [...] Read more.

Systemic inflammation can be triggered by infection, surgery, trauma or burns. During systemic inflammation, an overshooting immune response induces tissue damage resulting in organ dysfunction and mortality. Endothelial cells make up the inner lining of all blood vessels and are critically involved in maintaining organ integrity by regulating tissue perfusion. Permeability of the endothelial monolayer is strictly controlled and highly organ-specific, forming continuous, fenestrated and discontinuous capillaries that orchestrate the extravasation of fluids, proteins and solutes to maintain organ homeostasis. In the physiological state, the endothelial barrier is maintained by the glycocalyx, extracellular matrix and intercellular junctions including adherens and tight junctions. As endothelial cells are constantly sensing and responding to the extracellular environment, their activation by inflammatory stimuli promotes a loss of endothelial barrier function, which has been identified as a hallmark of systemic inflammation, leading to tissue edema formation and hypotension and thus, is a key contributor to lethal outcomes. In this review, we provide a comprehensive summary of the major players, such as the angiopoietin-Tie2 signaling axis, adrenomedullin and vascular endothelial (VE-) cadherin, that substantially contribute to the regulation and dysregulation of endothelial permeability during systemic inflammation and elucidate treatment strategies targeting the preservation of vascular integrity. Full article

(This article belongs to the Special Issue The Maladaptive Immune Response in Innate and Adaptive Immunity during Systemic Inflammation)

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26 pages, 1632 KiB

Open AccessReview

The Fatal Circle of NETs and NET-Associated DAMPs Contributing to Organ Dysfunction

by Helena Block, Jan Rossaint and Alexander Zarbock

Cells 2022, 11(12), 1919; https://doi.org/10.3390/cells11121919 - 14 Jun 2022

Cited by 24 | Viewed by 3602

Abstract

The innate immune system is the first line of defense against invading pathogens or sterile injuries. Pattern recognition receptors (PRR) sense molecules released from inflamed or damaged cells, or foreign molecules resulting from invading pathogens. PRRs can in turn induce inflammatory responses, comprising [...] Read more.

The innate immune system is the first line of defense against invading pathogens or sterile injuries. Pattern recognition receptors (PRR) sense molecules released from inflamed or damaged cells, or foreign molecules resulting from invading pathogens. PRRs can in turn induce inflammatory responses, comprising the generation of cytokines or chemokines, which further induce immune cell recruitment. Neutrophils represent an essential factor in the early immune response and fulfill numerous tasks to fight infection or heal injuries. The release of neutrophil extracellular traps (NETs) is part of it and was originally attributed to the capture and elimination of pathogens. In the last decade studies revealed a detrimental role of NETs during several diseases, often correlated with an exaggerated immune response. Overwhelming inflammation in single organs can induce remote organ damage, thereby further perpetuating release of inflammatory molecules. Here, we review recent findings regarding damage-associated molecular patterns (DAMPs) which are able to induce NET formation, as well as NET components known to act as DAMPs, generating a putative fatal circle of inflammation contributing to organ damage and sequentially occurring remote organ injury. Full article

(This article belongs to the Special Issue The Maladaptive Immune Response in Innate and Adaptive Immunity during Systemic Inflammation)

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32 pages, 1714 KiB

Open AccessReview

Immune Cell Plasticity in Inflammation: Insights into Description and Regulation of Immune Cell Phenotypes

by Andreas Margraf and Mauro Perretti

Cells 2022, 11(11), 1824; https://doi.org/10.3390/cells11111824 - 02 Jun 2022

Cited by 9 | Viewed by 4149

Abstract

Inflammation is a life-saving immune reaction occurring in response to invading pathogens. Nonetheless, inflammation can also occur in an uncontrolled, unrestricted manner, leading to chronic disease and organ damage. Mechanisms triggering an inflammatory response, hindering such a response, or leading to its resolution [...] Read more.

Inflammation is a life-saving immune reaction occurring in response to invading pathogens. Nonetheless, inflammation can also occur in an uncontrolled, unrestricted manner, leading to chronic disease and organ damage. Mechanisms triggering an inflammatory response, hindering such a response, or leading to its resolution are well-studied but so far insufficiently elucidated with regard to precise therapeutic interventions. Notably, as an immune reaction evolves, requirements and environments for immune cells change, and thus cellular phenotypes adapt and shift, leading to the appearance of distinct cellular subpopulations with new functional features. In this article, we aim to highlight properties of, and overarching regulatory factors involved in, the occurrence of immune cell phenotypes with a special focus on neutrophils, macrophages and platelets. Additionally, we point out implications for both diagnostics and therapeutics in inflammation research. Full article

(This article belongs to the Special Issue The Maladaptive Immune Response in Innate and Adaptive Immunity during Systemic Inflammation)

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