Trypanosoma Brucei secreted aromatic ketoacids represent novel therapies for inflammatory diseases through suppression of pro-inflammatory responses in primary human immune cells.

The extracellular parasite and causative agent of African sleeping sickness Trypanosoma brucei (T. brucei) has evolved a number of strategies to avoid immune detection in the host. One recently described mechanism involves the conversion of host-derived amino acids to aromatic ketoacids, which are detected at relatively high concentrations in the bloodstream of infected individuals. These ketoacids have been shown to directly suppress inflammatory responses in murine immune cells, as well as acting as potent inducers of the stress response enzyme, heme oxygenase 1 (HO-1), which has proven anti-inflammatory properties. The aim of this study was to investigate the immunomodulatory properties of the T. brucei-derived ketoacids in primary human immune cells and further examine their potential as a therapy for inflammatory diseases. We report that the T. brucei-derived ketoacids, indole pyruvate (IP) and hydroxyphenylpyruvate (HPP), induce HO-1 expression through Nrf2 activation in human dendritic cells (DC). They also limit DC maturation and suppress the production of pro-inflammatory cytokines, which, in turn, leads to a reduced capacity to differentiate adaptive CD4+ T cells. Furthermore, the ketoacids are capable of modulating DC cellular metabolism and suppressing the inflammatory profile of cells isolated from patients with inflammatory bowel disease. This study therefore not only provides further evidence of the immune-evasion mechanisms employed by T. brucei, but also supports further exploration of this new class of HO-1 inducers as potential therapeutics for the treatment of inflammatory conditions.

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Succinate Is an Inflammation-Induced Immunoregulatory Metabolite in Macrophages

Metabolites ◽

10.3390/metabo10090372 ◽

2020 ◽

Vol 10 (9) ◽

pp. 372 ◽

Cited By ~ 2

Author(s):

Karl J. Harber ◽

Kyra E. de Goede ◽

Sanne G. S. Verberk ◽

Elisa Meinster ◽

Helga E. de Vries ◽

...

Keyword(s):

Immune Responses ◽

Immune Cells ◽

Immune Cell ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Cell Phenotype ◽

Independent Manner ◽

Inflammatory Macrophages ◽

Necrosis Factor

Immunometabolism revealed the crucial role of cellular metabolism in controlling immune cell phenotype and functions. Macrophages, key immune cells that support progression of numerous inflammatory diseases, have been well described as undergoing vast metabolic rewiring upon activation. The immunometabolite succinate particularly gained a lot of attention and emerged as a crucial regulator of macrophage responses and inflammation. Succinate was originally described as a metabolite that supports inflammation via distinct routes. Recently, studies have indicated that succinate and its receptor SUCNR1 can suppress immune responses as well. These apparent contradictory effects might be due to specific experimental settings and particularly the use of distinct succinate forms. We therefore compared the phenotypic and functional effects of distinct succinate forms and receptor mouse models that were previously used for studying succinate immunomodulation. Here, we show that succinate can suppress secretion of inflammatory mediators IL-6, tumor necrosis factor (TNF) and nitric oxide (NO), as well as inhibit Il1b mRNA expression of inflammatory macrophages in a SUCNR1-independent manner. We also observed that macrophage SUCNR1 deficiency led to an enhanced inflammatory response without addition of exogenous succinate. While our study does not reveal new mechanistic insights into how succinate elicits different inflammatory responses, it does indicate that the inflammatory effects of succinate and its receptor SUCNR1 in macrophages are clearly context dependent.

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HDL in Immune-Inflammatory Responses: Implications beyond Cardiovascular Diseases

Cells ◽

10.3390/cells10051061 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1061

Author(s):

Fabrizia Bonacina ◽

Angela Pirillo ◽

Alberico L. Catapano ◽

Giuseppe D. Norata

Keyword(s):

Immune Cells ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Membrane Lipid ◽

High Density Lipoproteins ◽

Protective Effects ◽

The Road ◽

Plasma Membrane Lipid ◽

Inflammatory Burden

High density lipoproteins (HDL) are heterogeneous particles composed by a vast array of proteins and lipids, mostly recognized for their cardiovascular (CV) protective effects. However, evidences from basic to clinical research have contributed to depict a role of HDL in the modulation of immune-inflammatory response thus paving the road to investigate their involvement in other diseases beyond those related to the CV system. HDL-C levels and HDL composition are indeed altered in patients with autoimmune diseases and usually associated to disease severity. At molecular levels, HDL have been shown to modulate the anti-inflammatory potential of endothelial cells and, by controlling the amount of cellular cholesterol, to interfere with the signaling through plasma membrane lipid rafts in immune cells. These findings, coupled to observations acquired from subjects carrying mutations in genes related to HDL system, have helped to elucidate the contribution of HDL beyond cholesterol efflux thus posing HDL-based therapies as a compelling interventional approach to limit the inflammatory burden of immune-inflammatory diseases.

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Osteopontin and Mucosal Protection

Journal of Dental Research ◽

10.1177/154405910608500503 ◽

2006 ◽

Vol 85 (5) ◽

pp. 404-415 ◽

Cited By ~ 51

Author(s):

J. Sodek ◽

A. Paes Batista Da Silva ◽

R. Zohar

Keyword(s):

Immune Cells ◽

Barrier Function ◽

Inflammatory Responses ◽

Current Knowledge ◽

Inflammatory Diseases ◽

Biological Activities ◽

Proteolytic Processing ◽

Mucosal Inflammation ◽

Tissue Destruction ◽

Mucosal Tissues

Protection of mucosal tissues of the oral cavity, intestines, respiratory tract, and urogenital tract from the constant challenge of pathogens is achieved by the combined barrier function of the lining epithelia and specialized immune cells. Recent studies have indicated that osteopontin (OPN) has a pivotal role in the development of immune responses and in the tissue destruction and the subsequent repair processes associated with inflammatory diseases. While expression of OPN is increased in immune cells—including neutrophils, macrophages, T- and B-lymphocytes—and in epithelial, endothelial, and fibroblastic cells of inflamed tissues, deciphering the specific functions of OPN has been difficult. In part, this is due to the broad range of biological activities of OPN that are mediated by multiple receptors which recognize several signaling motifs whose activities are influenced by post-translational modifications and proteolytic processing of OPN. Understanding the role of OPN in mucosal inflammation is further complicated by its contributions to the barrier function of the lining epithelia and the complexity of the specialized mucosal immune system. In an attempt to provide some insights into the involvement of OPN in mucosal diseases, this review summarizes current knowledge of the biological activities of OPN involved in the development of inflammatory responses and in wound healing, and indicates how these activities may affect the protection of mucosal tissues.

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In Vivo Targeting of CXCR4—New Horizons

Cancers ◽

10.3390/cancers13235920 ◽

2021 ◽

Vol 13 (23) ◽

pp. 5920

Author(s):

Margret Schottelius ◽

Ken Herrmann ◽

Constantin Lapa

Keyword(s):

Immune Cells ◽

Immune Cell ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Clinical Status ◽

Inflammatory Stimuli ◽

Imaging Probes ◽

Recent Developments ◽

Chemokine Receptor 4

Given its pre-eminent role in the context of tumor cell growth as well as metastasis, the C-X-C motif chemokine receptor 4 (CXCR4) has attracted a lot of interest in the field of nuclear oncology, and clinical evidence on the high potential of CXCR4-targeted theranostics is constantly accumulating. Additionally, since CXCR4 also represents a key player in the orchestration of inflammatory responses to inflammatory stimuli, based on its expression on a variety of pro- and anti-inflammatory immune cells (e.g., macrophages and T-cells), CXCR4-targeted inflammation imaging has recently gained considerable attention. Therefore, after briefly summarizing the current clinical status quo of CXCR4-targeted theranostics in cancer, this review primarily focuses on imaging of a broad spectrum of inflammatory diseases via the quantification of tissue infiltration with CXCR4-expressing immune cells. An up-to-date overview of the ongoing preclinical and clinical efforts to visualize inflammation and its resolution over time is provided, and the predictive value of the CXCR4-associated imaging signal for disease outcome is discussed. Since the sensitivity and specificity of CXCR4-targeted immune cell imaging greatly relies on the availability of suitable, tailored imaging probes, recent developments in the field of CXCR4-targeted imaging agents for various applications are also addressed.

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Dooming Phagocyte Responses: Inflammatory Effects of Endogenous Oxidized Phospholipids

Frontiers in Endocrinology ◽

10.3389/fendo.2021.626842 ◽

2021 ◽

Vol 12 ◽

Author(s):

Marco Di Gioia ◽

Ivan Zanoni

Keyword(s):

Immune Cells ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Biological Activities ◽

Oxidized Lipids ◽

Oxidized Phospholipids ◽

Clinical Tools ◽

Stress Mediators ◽

The Impact

Endogenous oxidized phospholipids are produced during tissue stress and are responsible for sustaining inflammatory responses in immune as well as non-immune cells. Their local and systemic production and accumulation is associated with the etiology and progression of several inflammatory diseases, but the molecular mechanisms that underlie the biological activities of these oxidized phospholipids remain elusive. Increasing evidence highlights the ability of these stress mediators to modulate cellular metabolism and pro-inflammatory signaling in phagocytes, such as macrophages and dendritic cells, and to alter the activation and polarization of these cells. Because these immune cells serve a key role in maintaining tissue homeostasis and organ function, understanding how endogenous oxidized lipids reshape phagocyte biology and function is vital for designing clinical tools and interventions for preventing, slowing down, or resolving chronic inflammatory disorders that are driven by phagocyte dysfunction. Here, we discuss the metabolic and signaling processes elicited by endogenous oxidized lipids and outline new hypotheses and models to elucidate the impact of these lipids on phagocytes and inflammation.

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Lysosomal amino acid transporters as key players in inflammatory diseases

International Immunology ◽

10.1093/intimm/dxab069 ◽

2021 ◽

Author(s):

Noriko Toyama-Sorimachi ◽

Toshihiko Kobayashi

Keyword(s):

Signal Transduction ◽

Amino Acid ◽

Immune Cells ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Metabolic Adaptation ◽

Amino Acid Transporters ◽

Proof Of Concept ◽

Immune Mediated ◽

Solute Carrier

Abstract Controlling inflammation can alleviate immune-mediated, lifestyle-related and neurodegenerative diseases. The endolysosome system plays critical roles in inflammatory responses. Endolysosomes function as signal transduction hubs to convert various environmental danger signals into gene expression, enabling metabolic adaptation of immune cells and efficient orchestration of inflammation. Solute carrier family 15 member 3 (SLC15A3) and member 4 (SLC15A4) are endolysosome-resident amino acid transporters that are preferentially expressed in immune cells. These transporters play essential roles in signal transduction through endolysosomes, and the loss of either transporter can alleviate multiple inflammatory diseases because of perturbed endolysosome-dependent signaling events, including inflammatory and metabolic signaling. Here, we summarize the findings leading to a proof-of-concept for anti-inflammatory strategies based on targeting SLC15 transporters.

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Clinically Relevant Radiation Exposure Differentially Impacts Forms of Cell Death in Human Cells of the Innate and Adaptive Immune System

International Journal of Molecular Sciences ◽

10.3390/ijms19113574 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3574 ◽

Cited By ~ 20

Author(s):

Sylvia Falcke ◽

Paul Rühle ◽

Lisa Deloch ◽

Rainer Fietkau ◽

Benjamin Frey ◽

...

Keyword(s):

Cell Death ◽

Radiation Therapy ◽

Immune Cells ◽

Inflammatory Diseases ◽

Dose Range ◽

Adaptive Immune System ◽

High Dose ◽

Radiation Doses ◽

Human Immune

In cancer treatments, especially high-dose radiotherapy (HDRT) is applied. Patients suffering from chronic inflammatory diseases benefit from low-dose radiation therapy (LDRT), but exposure to very low radiation doses can still steadily increase for diagnostic purposes. Yet, little is known about how radiation impacts on forms of cell death in human immune cells. In this study, the radiosensitivity of human immune cells of the peripheral blood was examined in a dose range from 0.01 to 60 Gy with regard to induction of apoptosis, primary necrosis, and secondary necrosis. Results showed that immune cells differed in their radiosensitivity, with monocytes being the most radioresistant. T cells mainly died by necrosis and were moderately radiosensitive. This was followed by B and natural killer (NK) cells, which died mainly by apoptosis. X-radiation had no impact on cell death in immune cells at very low doses (≤0.1 Gy). Radiation doses of LDRT (0.3–0.7 Gy) impacted on the more radiosensitive NK and B cells, which might contribute to attenuation of inflammation. Even single doses applied during RT of tumors did not erase the immune cells completely. These in vitro studies can be considered as the basis to optimize individual radiation therapy schemes in multimodal settings and to define suited time points for further inclusion of immunotherapies.

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Role of MIF in myocardial ischaemia and infarction: insight from recent clinical and experimental findings

Clinical Science ◽

10.1042/cs20130828 ◽

2014 ◽

Vol 127 (3) ◽

pp. 149-161 ◽

Cited By ~ 31

Author(s):

Nalin H. Dayawansa ◽

Xiao-Ming Gao ◽

David A. White ◽

Anthony M. Dart ◽

Xiao-Jun Du

Keyword(s):

Myocardial Ischaemia ◽

Immune Cells ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Metabolic Activation ◽

Infarct Healing ◽

Acute Mi ◽

Antioxidative Stress ◽

Experimental Findings

First discovered in 1966 as an inflammatory cytokine, MIF (macrophage migration inhibitory factor) has been extensively studied for its pivotal role in a variety of inflammatory diseases, including rheumatoid arthritis and atherosclerosis. Although initial studies over a decade ago reported increases in circulating MIF levels following acute MI (myocardial infarction), the dynamic changes in MIF and its pathophysiological significance following MI have been unknown until recently. In the present review, we summarize recent experimental and clinical studies examining the diverse functions of MIF across the spectrum of acute MI from brief ischaemia to post-infarct healing. Following an acute ischaemic insult, MIF is rapidly released from jeopardized cardiomyocytes, followed by a persistent MIF production and release from activated immune cells, resulting in a sustained increase in circulating levels of MIF. Recent studies have documented two distinct actions of MIF following acute MI. In the supra-acute phase of ischaemia, MIF mediates cardioprotection via several distinct mechanisms, including metabolic activation, apoptosis suppression and antioxidative stress. In prolonged myocardial ischaemia, however, MIF promotes inflammatory responses with largely detrimental effects on cardiac function and remodelling. The pro-inflammatory properties of MIF are complex and involve MIF derived from cardiac and immune cells contributing sequentially to the innate immune response evoked by MI. Emerging evidence on the role of MIF in myocardial ischaemia and infarction highlights a significant potential for the clinical use of MIF agonists or antagonists and as a unique cardiac biomarker.

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The fate of influenza A virus after infection of human macrophages and dendritic cells

Journal of General Virology ◽

10.1099/vir.0.045021-0 ◽

2012 ◽

Vol 93 (11) ◽

pp. 2315-2325 ◽

Cited By ~ 39

Author(s):

Kirsty R. Short ◽

Andrew G. Brooks ◽

Patrick C. Reading ◽

Sarah L. Londrigan

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Influenza A Virus ◽

Immune Cells ◽

Influenza A ◽

Inflammatory Responses ◽

Critical Role ◽

Virus Release ◽

Adaptive Immune ◽

Human Immune

Airway macrophages (MΦ) and dendritic cells (DC) are important components of the innate host defence. Historically, these immune cells have been considered to play a critical role in controlling the severity of influenza A virus (IAV) infection by limiting virus release, initiating local inflammatory responses and by priming subsequent adaptive immune responses. However, some IAV strains have been reported to replicate productively in human immune cells. Potential amplification and dissemination of IAV from immune cells may therefore be an important virulence determinant. Herein, we will review findings in relation to the fate of IAV following infection of MΦ and DC. Insights regarding the consequences and outcomes of IAV infection of airway MΦ and DC are discussed in order to gain a better understanding of the pathogenesis of influenza virus.

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