Succinate Is an Inflammation-Induced Immunoregulatory Metabolite in Macrophages

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.

Download Full-text

The Role of Src Kinase in Macrophage-Mediated Inflammatory Responses

Mediators of Inflammation ◽

10.1155/2012/512926 ◽

2012 ◽

Vol 2012 ◽

pp. 1-18 ◽

Cited By ~ 115

Author(s):

Se Eun Byeon ◽

Young-Su Yi ◽

Jueun Oh ◽

Byong Chul Yoo ◽

Sungyoul Hong ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Immune Responses ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Src Kinase ◽

Multiple Roles ◽

Cellular Migration ◽

Pharmaceutical Drugs ◽

Tyrosine Protein Kinase

Src kinase (Src) is a tyrosine protein kinase that regulates cellular metabolism, survival, and proliferation. Many studies have shown that Src plays multiple roles in macrophage-mediated innate immunity, such as phagocytosis, the production of inflammatory cytokines/mediators, and the induction of cellular migration, which strongly implies that Src plays a pivotal role in the functional activation of macrophages. Macrophages are involved in a variety of immune responses and in inflammatory diseases including rheumatoid arthritis, atherosclerosis, diabetes, obesity, cancer, and osteoporosis. Previous studies have suggested roles for Src in macrophage-mediated inflammatory responses; however, recently, new functions for Src have been reported, implying that Src functions in macrophage-mediated inflammatory responses that have not been described. In this paper, we discuss recent studies regarding a number of these newly defined functions of Src in macrophage-mediated inflammatory responses. Moreover, we discuss the feasibility of Src as a target for the development of new pharmaceutical drugs to treat macrophage-mediated inflammatory diseases. We provide insights into recent reports regarding new functions for Src that are related to macrophage-related inflammatory responses and the development of novel Src inhibitors with strong immunosuppressive and anti-inflammatory properties, which could be applied to various macrophage-mediated inflammatory diseases.

Download Full-text

Niacin protects against abdominal aortic aneurysm formation via GPR109A independent mechanisms: role of NAD+/nicotinamide

Cardiovascular Research ◽

10.1093/cvr/cvz303 ◽

2019 ◽

Vol 116 (14) ◽

pp. 2226-2238 ◽

Cited By ~ 5

Author(s):

Tetsuo Horimatsu ◽

Andra L Blomkalns ◽

Mourad Ogbi ◽

Mary Moses ◽

David Kim ◽

...

Keyword(s):

Immune Cells ◽

Inflammatory Cell ◽

Immune Cell ◽

Inflammatory Responses ◽

Aortic Aneurysms ◽

Cell Infiltration ◽

Protective Effects ◽

Abdominal Aortic ◽

G Protein Coupled

Abstract Aims Chronic adventitial and medial infiltration of immune cells play an important role in the pathogenesis of abdominal aortic aneurysms (AAAs). Nicotinic acid (niacin) was shown to inhibit atherosclerosis by activating the anti-inflammatory G protein-coupled receptor GPR109A [also known as hydroxycarboxylic acid receptor 2 (HCA2)] expressed on immune cells, blunting immune activation and adventitial inflammatory cell infiltration. Here, we investigated the role of niacin and GPR109A in regulating AAA formation. Methods and results Mice were supplemented with niacin or nicotinamide, and AAA was induced by angiotensin II (AngII) infusion or calcium chloride (CaCl2) application. Niacin markedly reduced AAA formation in both AngII and CaCl2 models, diminishing adventitial immune cell infiltration, concomitant inflammatory responses, and matrix degradation. Unexpectedly, GPR109A gene deletion did not abrogate the protective effects of niacin against AAA formation, suggesting GPR109A-independent mechanisms. Interestingly, nicotinamide, which does not activate GPR109A, also inhibited AAA formation and phenocopied the effects of niacin. Mechanistically, both niacin and nicotinamide supplementation increased nicotinamide adenine dinucleotide (NAD+) levels and NAD+-dependent Sirt1 activity, which were reduced in AAA tissues. Furthermore, pharmacological inhibition of Sirt1 abrogated the protective effect of nicotinamide against AAA formation. Conclusion Niacin protects against AAA formation independent of GPR109A, most likely by serving as an NAD+ precursor. Supplementation of NAD+ using nicotinamide-related biomolecules may represent an effective and well-tolerated approach to preventing or treating AAA.

Download Full-text

Deficient CD40-TRAF6 signaling in leukocytes prevents atherosclerosis by skewing the immune response toward an antiinflammatory profile

Journal of Experimental Medicine ◽

10.1084/jem.20091293 ◽

2010 ◽

Vol 207 (2) ◽

pp. 391-404 ◽

Cited By ~ 163

Author(s):

Esther Lutgens ◽

Dirk Lievens ◽

Linda Beckers ◽

Erwin Wijnands ◽

Oliver Soehnlein ◽

...

Keyword(s):

Immune Responses ◽

Inflammatory Diseases ◽

Tumor Necrosis Factor Receptor ◽

Cd40 Ligand ◽

Therapeutic Effects ◽

Signaling Axis ◽

Plaque Phenotype ◽

Necrosis Factor

The CD40–CD40 ligand (CD40L) signaling axis plays an important role in immunological pathways. Consequently, this dyad is involved in chronic inflammatory diseases, including atherosclerosis. Inhibition of CD40L in apolipoprotein E (Apoe)–deficient (Apoe−/−) mice not only reduced atherosclerosis but also conferred a clinically favorable plaque phenotype that was low in inflammation and high in fibrosis. Blockade of CD40L may not be therapeutically feasible, as long-term inhibition will compromise systemic immune responses. Conceivably, more targeted intervention strategies in CD40 signaling will have less deleterious side effects. We report that deficiency in hematopoietic CD40 reduces atherosclerosis and induces features of plaque stability. To elucidate the role of CD40–tumor necrosis factor receptor-associated factor (TRAF) signaling in atherosclerosis, we examined disease progression in mice deficient in CD40 and its associated signaling intermediates. Absence of CD40-TRAF6 but not CD40-TRAF2/3/5 signaling abolishes atherosclerosis and confers plaque fibrosis in Apoe−/− mice. Mice with defective CD40-TRAF6 signaling display a reduced blood count of Ly6Chigh monocytes, an impaired recruitment of Ly6C+ monocytes to the arterial wall, and polarization of macrophages toward an antiinflammatory regulatory M2 signature. These data unveil a role for CD40–TRAF6, but not CD40–TRAF2/3/5, interactions in atherosclerosis and establish that targeting specific components of the CD40–CD40L pathway harbors the potential to achieve therapeutic effects in atherosclerosis.

Download Full-text

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.

Download Full-text

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.

Download Full-text

Dietary and Physiological Effects of Zinc on the Immune System

Annual Review of Nutrition ◽

10.1146/annurev-nutr-122019-120635 ◽

2021 ◽

Vol 41 (1) ◽

Author(s):

Inga Wessels ◽

Henrike Josephine Fischer ◽

Lothar Rink

Keyword(s):

Immune Responses ◽

Immune Cells ◽

Immune Cell ◽

Current Knowledge ◽

Annual Review ◽

Publication Date ◽

Biological Processes ◽

And Function ◽

Broad Overview

Evidence for the importance of zinc for all immune cells and for mounting an efficient and balanced immune response to various environmental stressors has been accumulating in recent years. This article describes the role of zinc in fundamental biological processes and summarizes our current knowledge of zinc's effect on hematopoiesis, including differentiation into immune cell subtypes. In addition, the important role of zinc during activation and function of immune cells is detailed and associated with the specific immune responses to bacteria, parasites, and viruses. The association of zinc with autoimmune reactions and cancers as diseases with increased or decreased immune responses is also discussed. This article provides a broad overview of the manifold roles that zinc, or its deficiency, plays in physiology and during various diseases. Consequently, we discuss why zinc supplementation should be considered, especially for people at risk of deficiency. Expected final online publication date for the Annual Review of Nutrition, Volume 41 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Download Full-text

Targeting Versican as a Potential Immunotherapeutic Strategy in the Treatment of Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.712807 ◽

2021 ◽

Vol 11 ◽

Author(s):

Priyanka Hirani ◽

Valentine Gauthier ◽

Carys E. Allen ◽

Thomas N. Wight ◽

Oliver M. T. Pearce

Keyword(s):

Immune Cell ◽

Inflammatory Diseases ◽

Tumour Progression ◽

Cell Phenotype ◽

Direct Role ◽

Post Translational Modifications ◽

Tumour Immunity ◽

Immunotherapeutic Strategy ◽

Immunotherapy Target

A growing body of literature links events associated with the progression and severity of immunity and inflammatory disease with the composition of the tissue extracellular matrix as defined by the matrisome. One protein in the matrisome that is common to many inflammatory diseases is the large proteoglycan versican, whose varied function is achieved through multiple isoforms and post-translational modifications of glycosaminoglycan structures. In cancer, increased levels of versican are associated with immune cell phenotype, disease prognosis and failure to respond to treatment. Whether these associations between versican expression and tumour immunity are the result of a direct role in the pathogenesis of tumours is not clear. In this review, we have focused on the role of versican in the immune response as it relates to tumour progression, with the aim of determining whether our current understanding of the immunobiology of versican warrants further study as a cancer immunotherapy target.

Download Full-text

Herbal Plants: The Role of AhR in Mediating Immunomodulation

Frontiers in Immunology ◽

10.3389/fimmu.2021.697663 ◽

2021 ◽

Vol 12 ◽

Author(s):

Izzah Bungsu ◽

Nurolaini Kifli ◽

Siti Rohaiza Ahmad ◽

Hazim Ghani ◽

Anne Catherine Cunningham

Keyword(s):

Immune Responses ◽

Therapeutic Strategy ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Aryl Hydrocarbon ◽

Herbal Plants ◽

Inflammatory Bowel ◽

Cellular Immune

The prevalence of chronic inflammatory diseases including inflammatory bowel disease (IBD), autoimmunity and cancer have increased in recent years. Herbal-based compounds such as flavonoids have been demonstrated to contribute to the modulation of these diseases although understanding their mechanism of action remains limited. Flavonoids are able to interact with cellular immune components in a distinct way and influence immune responses at a molecular level. In this mini review, we highlight recent progress in our understanding of the modulation of immune responses by the aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor whose activity can be regulated by diverse molecules including flavonoids. We focus on the role of AhR in integrating signals from flavonoids to modulate inflammatory responses using in vitro and experimental animal models. We also summarize the limitations of these studies. Medicinal herbs have been widely used to treat inflammatory disorders and may offer a valuable therapeutic strategy to treat aberrant inflammatory responses by modulation of the AhR pathway.

Download Full-text

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.

Download Full-text

Dual-Specificity Phosphatases in Immunity and Infection: An Update

International Journal of Molecular Sciences ◽

10.3390/ijms20112710 ◽

2019 ◽

Vol 20 (11) ◽

pp. 2710 ◽

Cited By ~ 15

Author(s):

Roland Lang ◽

Faizal Raffi

Keyword(s):

Immune Responses ◽

Immune Cells ◽

Knockout Mice ◽

Cell Activation ◽

Immune Cell ◽

Inflammatory Responses ◽

Selective Inhibition ◽

Dual Specificity ◽

Mitogen Activated Protein ◽

Dual Specificity Phosphatases

Kinase activation and phosphorylation cascades are key to initiate immune cell activation in response to recognition of antigen and sensing of microbial danger. However, for balanced and controlled immune responses, the intensity and duration of phospho-signaling has to be regulated. The dual-specificity phosphatase (DUSP) gene family has many members that are differentially expressed in resting and activated immune cells. Here, we review the progress made in the field of DUSP gene function in regulation of the immune system during the last decade. Studies in knockout mice have confirmed the essential functions of several DUSP-MAPK phosphatases (DUSP-MKP) in controlling inflammatory and anti-microbial immune responses and support the concept that individual DUSP-MKP shape and determine the outcome of innate immune responses due to context-dependent expression and selective inhibition of different mitogen-activated protein kinases (MAPK). In addition to the canonical DUSP-MKP, several small-size atypical DUSP proteins regulate immune cells and are therefore also reviewed here. Unexpected and complex findings in DUSP knockout mice pose new questions regarding cell type-specific and redundant functions. Another emerging question concerns the interaction of DUSP-MKP with non-MAPK binding partners and substrate proteins. Finally, the pharmacological targeting of DUSPs is desirable to modulate immune and inflammatory responses.

Download Full-text