Osteopontin and Mucosal Protection

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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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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Nuclear receptor Nur77: its role in chronic inflammatory diseases

Essays in Biochemistry ◽

10.1042/ebc20210004 ◽

2021 ◽

Author(s):

Sanne C. Lith ◽

Carlie J.M. de Vries

Keyword(s):

Nuclear Receptor ◽

Inflammatory Disease ◽

Inflammatory Responses ◽

Current Knowledge ◽

Inflammatory Diseases ◽

Cell Types ◽

Experimental Models ◽

Therapeutic Interventions ◽

Alternative Mechanism ◽

Signaling Complex

Abstract Nur77 is a nuclear receptor that has been implicated as a regulator of inflammatory disease. The expression of Nur77 increases upon stimulation of immune cells and is differentially expressed in chronically inflamed organs in human and experimental models. Furthermore, in a variety of animal models dedicated to study inflammatory diseases, changes in Nur77 expression alter disease outcome. The available studies comprise a wealth of information on the function of Nur77 in diverse cell types and tissues. Negative cross-talk of Nur77 with the NFκB signaling complex is an example of Nur77 effector function. An alternative mechanism of action has been established, involving Nur77-mediated modulation of metabolism in macrophages as well as in T cells. In this review, we summarize our current knowledge on the role of Nur77 in atherosclerosis, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and sepsis. Detailed insight in the control of inflammatory responses will be essential in order to advance Nur77-targeted therapeutic interventions in inflammatory disease.

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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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In Vitro and In Vivo Immunomodulator Activities of Allium sativum L.

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/4984659 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 9

Author(s):

Mouna Moutia ◽

Norddine Habti ◽

Abdallah Badou

Keyword(s):

Immune Cells ◽

Allium Sativum ◽

Therapeutic Potential ◽

Inflammatory Diseases ◽

Biological Activities ◽

Antioxidant Properties ◽

Allergic Airway Inflammation ◽

Cytokine Gene Expression

Allium Sativum L. (garlic), which is a species of the onion family, Alliaceae, is one of the most used plants in traditional medicine worldwide. More than 200 chemicals with diverse properties have been found in garlic extracts. Several garlic compounds were suggested to be efficient in improving various pathologies including certain types of cancer. This paper is an overview of data about garlic biological activities in vitro and/or in vivo on immune cells, on the development of certain inflammatory diseases, and on different types of carcinomas and sarcomas. Garlic and its compounds were found to have notable antioxidant properties. Garlic therapeutic potential has also been studied in several inflammatory diseases such as allergic-airway inflammation, inflammatory bowel disease, arthritic rheumatism, and atherosclerosis. Furthermore, garlic was found to be able to maintain the immune system homeostasis and to exhibit beneficial effects on immune cells especially through regulation of proliferation and cytokine gene expression. Finally, we will show how major garlic components such as sulfur compounds and polyphenols might be responsible for the garlic biological activities revealed in different situations. If identified, specific compounds present in garlic could potentially be used in therapy.

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TWEAK/Fn14 Activation Participates in Skin Inflammation

Mediators of Inflammation ◽

10.1155/2017/6746870 ◽

2017 ◽

Vol 2017 ◽

pp. 1-12 ◽

Cited By ~ 17

Author(s):

Qilu Liu ◽

Shengxiang Xiao ◽

Yumin Xia

Keyword(s):

Cell Fate ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Biological Activities ◽

Inflammatory Cells ◽

Skin Inflammation ◽

Tnf Receptor ◽

Inflammatory Infiltration ◽

Papillomavirus Infection ◽

Chemotactic Protein

Tumor necrosis factor- (TNF-) like weak inducer of apoptosis (TWEAK) participates in multiple biological activities via binding to its sole receptor—fibroblast growth factor-inducible 14 (Fn14). The TWEAK/Fn14 signaling pathway is activated in skin inflammation and modulates the inflammatory responses of keratinocytes by activating nuclear factor-κB signals and enhancing the production of several cytokines, including interleukins, monocyte chemotactic protein-1, RANTES (regulated on activation, normal T cell expressed and secreted), and interferon gamma-induced protein 10. Mild or transient TWEAK/Fn14 activation contributes to tissular repair and regeneration while excessive or persistent TWEAK/Fn14 signals may lead to severe inflammatory infiltration and tissue damage. TWEAK also regulates cell fate of keratinocytes, involving the function of Fn14-TNF receptor-associated factor-TNF receptor axis. By recruiting inflammatory cells, promoting cytokine production, and regulating cell fate, TWEAK/Fn14 activation plays a pivotal role in the pathogenesis of various skin disorders, such as psoriasis, atopic dermatitis, cutaneous vasculitis, human papillomavirus infection and related skin tumors, and cutaneous autoimmune diseases. Therefore, the TWEAK/Fn14 pathway may be a potential target for the development of novel therapeutics for skin inflammatory diseases.

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Aspirin and P2Y12 Inhibitors in platelet-mediated activation of neutrophils and monocytes

Thrombosis and Haemostasis ◽

10.1160/th14-11-0943 ◽

2015 ◽

Vol 114 (09) ◽

pp. 478-789 ◽

Cited By ~ 59

Author(s):

Waltraud Schrottmaier ◽

Julia Kral ◽

Sigrun Badrnya ◽

Alice Assinger

Keyword(s):

Immune Responses ◽

Antiplatelet Therapy ◽

Inflammatory Responses ◽

Current Knowledge ◽

Inflammatory Diseases ◽

Cardiovascular Complications ◽

P2y12 Inhibitors ◽

Beneficial Effects ◽

Cox Inhibitor ◽

The Impact

SummaryPlatelets are key players in haemostasis and represent a pivotal link between inflammation, immunity and atherogenesis. Depending on the (patho)physiological environment platelets modulate various leukocyte functions via release of inflammatory mediators and direct cell-cell interactions. Elevated levels of circulating platelet-leukocyte aggregates are found in patients suffering from several thrombotic or inflammatory conditions. Platelet-monocyte and platelet-neutrophil interaction can trigger pro- and anti-inflammatory responses and modulate effector functions of all leukocyte subpopulations. These platelet-mediated immune responses have implications for the progression of cardiovascular diseases and also play a crucial role during infections, cancer, transplantations and other inflammatory diseases of several organs. Antiplatelet therapy including the COX inhibitor aspirin and/or ADP receptor P2Y12 inhibitors such as clopidogrel, prasugrel and ticagrelor are the therapy of choice for various cardiovascular complications. Both aspirin and P2Y12 inhibitors attenuate platelet-leukocyte interactions, thereby also modulating immune responses. This may have beneficial effects in some pathological conditions, while it might be detrimental in others. This review aims to summarise the current knowledge on platelet-leukocyte interactions and the impact of aspirin and P2Y12 inhibition on platelet-mediated immune responses and to give an overview on the effects of antiplatelet therapy on platelet-leukocyte interplay in various diseases.

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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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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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Therapies Targeting Trained Immune Cells in Inflammatory and Autoimmune Diseases

Frontiers in Immunology ◽

10.3389/fimmu.2020.631743 ◽

2021 ◽

Vol 11 ◽

Author(s):

Cristina Municio ◽

Gabriel Criado

Keyword(s):

Autoimmune Diseases ◽

Immune Cells ◽

Inflammatory Diseases ◽

Cell Metabolism ◽

Innate Immune ◽

Epigenetic Reprogramming ◽

Innate Immune Cells ◽

Tissue Destruction ◽

Specific Stimulus ◽

Trained Immunity

The concept of trained immunity has recently emerged as a mechanism contributing to several immune mediated inflammatory conditions. Trained immunity is defined by the immunological memory developed in innate immune cells after a primary non-specific stimulus that, in turn, promotes a heightened inflammatory response upon a secondary challenge. The most characteristic changes associated to this process involve the rewiring of cell metabolism and epigenetic reprogramming. Under physiological conditions, the role of trained immune cells ensures a prompt response. This action is limited by effective resolution of inflammation and tissue repair in order to restore homeostasis. However, unrestrained activation of innate immune cells contributes to the development of chronic inflammation and tissue destruction through the secretion of inflammatory cytokines, proteases and growth factors. Therefore, interventions aimed at reversing the changes induced by trained immunity provide potential therapeutic approaches to treat inflammatory and autoimmune diseases like rheumatoid arthritis (RA). We review cellular approaches that target metabolism and the epigenetic reprogramming of dendritic cells, macrophages, natural killer cells, and other trained cells in the context of autoimmune inflammatory diseases.

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IL-1 Family Antagonists in Mouse and Human Skin Inflammation

Frontiers in Immunology ◽

10.3389/fimmu.2021.652846 ◽

2021 ◽

Vol 12 ◽

Author(s):

Praxedis Martin ◽

Jérémie D. Goldstein ◽

Loïc Mermoud ◽

Alejandro Diaz-Barreiro ◽

Gaby Palmer

Keyword(s):

Skin Diseases ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Current Knowledge ◽

Inflammatory Diseases ◽

Skin Inflammation ◽

Cell Type ◽

Inflammatory Skin Diseases ◽

Innate And Adaptive Immunity ◽

Skin Biology

Interleukin (IL)-1 family cytokines initiate inflammatory responses, and shape innate and adaptive immunity. They play important roles in host defense, but excessive immune activation can also lead to the development of chronic inflammatory diseases. Dysregulated IL-1 family signaling is observed in a variety of skin disorders. In particular, IL-1 family cytokines have been linked to the pathogenesis of psoriasis and atopic dermatitis. The biological activity of pro-inflammatory IL-1 family agonists is controlled by the natural receptor antagonists IL-1Ra and IL-36Ra, as well as by the regulatory cytokines IL-37 and IL-38. These four anti-inflammatory IL-1 family members are constitutively and highly expressed at steady state in the epidermis, where keratinocytes are a major producing cell type. In this review, we provide an overview of the current knowledge concerning their regulatory roles in skin biology and inflammation and their therapeutic potential in human inflammatory skin diseases. We further highlight some common misunderstandings and less well-known observations, which persist in the field despite recent extensive interest for these cytokines.

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