Immunometabolic function of cholesterol in cardiovascular disease and beyond

Abstract Inflammation represents the driving feature of many diseases, including atherosclerosis, cancer, autoimmunity and infections. It is now established that metabolic processes shape a proper immune response and within this context the alteration in cellular cholesterol homeostasis has emerged as a culprit of many metabolic abnormalities observed in chronic inflammatory diseases. Cholesterol accumulation supports the inflammatory response of myeloid cells (i.e. augmentation of toll-like receptor signalling, inflammasome activation, and production of monocytes and neutrophils) which is beneficial in the response to infections, but worsens diseases associated with chronic metabolic inflammation including atherosclerosis. In addition to the innate immune system, cells of adaptive immunity, upon activation, have also been shown to undergo a reprogramming of cellular cholesterol metabolism, which results in the amplification of inflammatory responses. Aim of this review is to discuss (i) the molecular mechanisms linking cellular cholesterol metabolism to specific immune functions; (ii) how cellular cholesterol accumulation sustains chronic inflammatory diseases such as atherosclerosis; (iii) the immunometabolic profile of patients with defects of genes affecting cholesterol metabolism including familial hypercholesterolaemia, cholesteryl ester storage disease, Niemann–Pick type C, and immunoglobulin D syndrome/mevalonate kinase deficiency. Available data indicate that cholesterol immunometabolism plays a key role in directing immune cells function and set the stage for investigating the repurposing of existing ‘metabolic’ drugs to modulate the immune response.

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Macrophage Polarization in Chronic Inflammatory Diseases: Killers or Builders?

Journal of Immunology Research ◽

10.1155/2018/8917804 ◽

2018 ◽

Vol 2018 ◽

pp. 1-25 ◽

Cited By ~ 95

Author(s):

Luca Parisi ◽

Elisabetta Gini ◽

Denisa Baci ◽

Marco Tremolati ◽

Matteo Fanuli ◽

...

Keyword(s):

Molecular Mechanisms ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Macrophage Polarization ◽

Cancer Type ◽

Effector Cells ◽

Chronic Inflammatory Diseases ◽

Pathological Conditions ◽

Cellular Components ◽

Cell Cell

Macrophages are key cellular components of the innate immunity, acting as the main player in the first-line defence against the pathogens and modulating homeostatic and inflammatory responses. Plasticity is a major feature of macrophages resulting in extreme heterogeneity both in normal and in pathological conditions. Macrophages are not homogenous, and they are generally categorized into two broad but distinct subsets as either classically activated (M1) or alternatively activated (M2). However, macrophages represent a continuum of highly plastic effector cells, resembling a spectrum of diverse phenotype states. Induction of specific macrophage functions is closely related to the surrounding environment that acts as a relevant orchestrator of macrophage functions. This phenomenon, termed polarization, results from cell/cell, cell/molecule interaction, governing macrophage functionality within the hosting tissues. Here, we summarized relevant cellular and molecular mechanisms driving macrophage polarization in “distant” pathological conditions, such as cancer, type 2 diabetes, atherosclerosis, and periodontitis that share macrophage-driven inflammation as a key feature, playing their dual role as killers (M1-like) and/or builders (M2-like). We also dissect the physio/pathological consequences related to macrophage polarization within selected chronic inflammatory diseases, placing polarized macrophages as a relevant hallmark, putative biomarkers, and possible target for prevention/therapy.

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Protein kinase networks that limit TLR signalling

Biochemical Society Transactions ◽

10.1042/bst20130124 ◽

2014 ◽

Vol 42 (1) ◽

pp. 11-24 ◽

Cited By ~ 15

Author(s):

Kristopher Clark

Keyword(s):

Immune Response ◽

Protein Kinase ◽

Molecular Mechanisms ◽

Inflammatory Diseases ◽

Nuclear Factor Κb ◽

Innate Immune ◽

Nuclear Factor ◽

Chronic Inflammatory Diseases ◽

Micro Organisms ◽

Tlr Signalling

TLRs (Toll-like receptors) detect invading micro-organisms which triggers the production of pro-inflammatory mediators needed to combat infection. Although these signalling networks are required to protect the host against invading pathogens, dysregulation of TLR pathways contributes to the development of chronic inflammatory diseases and autoimmune disorders. Molecular mechanisms have therefore evolved to restrict the strength of TLR signalling. In the present review, I highlight recent advances in our understanding of the protein kinase networks required to suppress the innate immune response by negatively regulating TLR signalling and/or promoting the secretion of anti-inflammatory cytokines. I present my discoveries on the key roles of the IKK (inhibitor of nuclear factor κB kinase)-related kinases and the SIKs (salt-inducible kinases) in limiting innate immunity within the greater context of the field.

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Techniques to Study Inflammasome Activation and Inhibition by Small Molecules

Molecules ◽

10.3390/molecules26061704 ◽

2021 ◽

Vol 26 (6) ◽

pp. 1704

Author(s):

Diego Angosto-Bazarra ◽

Cristina Molina-López ◽

Alejandro Peñín-Franch ◽

Laura Hurtado-Navarro ◽

Pablo Pelegrín

Keyword(s):

Inflammatory Response ◽

Small Molecules ◽

Mechanism Of Action ◽

Inflammatory Diseases ◽

Inflammasome Activation ◽

Chronic Inflammatory Diseases ◽

Anti Inflammatory ◽

Inhibitory Molecules ◽

Inflammasome Inhibitors

Inflammasomes are immune cytosolic oligomers involved in the initiation and progression of multiple pathologies and diseases. The tight regulation of these immune sensors is necessary to control an optimal inflammatory response and recover organism homeostasis. Prolonged activation of inflammasomes result in the development of chronic inflammatory diseases, and the use of small drug-like inhibitory molecules are emerging as promising anti-inflammatory therapies. Different aspects have to be taken in consideration when designing inflammasome inhibitors. This review summarizes the different techniques that can be used to study the mechanism of action of potential inflammasome inhibitory molecules.

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Unfulfilled Inflammatory Resolution: A Key Factor in the Pathogenesis of Psoriasis

Iranian Journal of Allergy Asthma and Immunology ◽

10.18502/ijaai.v19i4.4130 ◽

2020 ◽

Author(s):

Zohreh Jadali

Keyword(s):

Inflammatory Response ◽

Chronic Inflammation ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Relevant Literature ◽

Regulatory Mechanisms ◽

Immune Mediated ◽

Key Factor ◽

Inflammation Resolution

Recent literature has highlighted the importance of chronic inflammation in psoriasis pathogenesis. Non-resolving inflammation can trigger progressive tissue damage and inflammatory mediator release which in turn perpetuate the inflammatory cycle. Under normal conditions, inflammatory responses are tightly controlled through several mechanisms that restore normal tissue function and structure. Defects in regulatory mechanisms of the inflammatory response can result in persistent unresolved inflammation and further increases of inflammation. Therefore, this review focuses on defects in regulatory mechanisms of inflammatory responses that lead to uncontrolled chronic inflammation in psoriasis. Databases such as Pubmed Embase, ISI, and Iranian databases including Iranmedex, and SID were researched to identify relevant literature. The results of this review indicate that dysregulation of the inflammatory response may be a likely cause of various immune-mediated inflammatory disorders such as psoriasis. Based on current findings, advances in understanding the cellular and molecular mechanisms involved in inflammation resolution are not only improving our knowledge of the pathogenesis of chronic inflammatory diseases but also supporting the development of new therapeutic strategies.

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Tackling Chronic Inflammation with Withanolide Phytochemicals—A Withaferin A Perspective

Antioxidants ◽

10.3390/antiox9111107 ◽

2020 ◽

Vol 9 (11) ◽

pp. 1107

Author(s):

Emilie Logie ◽

Wim Vanden Berghe

Keyword(s):

Chronic Inflammation ◽

Molecular Mechanisms ◽

Inflammatory Diseases ◽

Withaferin A ◽

Related Factor ◽

Nuclear Factor ◽

Pharmaceutical Drugs ◽

In Vivo Models ◽

Chronic Inflammatory Diseases ◽

Anti Inflammatory

Chronic inflammatory diseases are considered to be one of the biggest threats to human health. Most prescribed pharmaceutical drugs aiming to treat these diseases are characterized by side-effects and negatively affect therapy adherence. Finding alternative treatment strategies to tackle chronic inflammation has therefore been gaining interest over the last few decades. In this context, Withaferin A (WA), a natural bioactive compound isolated from Withania somnifera, has been identified as a promising anti-cancer and anti-inflammatory compound. Although the majority of studies focus on the molecular mechanisms of WA in cancer models, recent evidence demonstrates that WA also holds promise as a new phytotherapeutic agent against chronic inflammatory diseases. By targeting crucial inflammatory pathways, including nuclear factor kappa B (NF-κB) and nuclear factor erythroid 2 related factor 2 (Nrf2) signaling, WA suppresses the inflammatory disease state in several in vitro and preclinical in vivo models of diabetes, obesity, neurodegenerative disorders, cystic fibrosis and osteoarthritis. This review provides a concise overview of the molecular mechanisms by which WA orchestrates its anti-inflammatory effects to restore immune homeostasis.

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Novel control of cAMP-regulated transcription in vascular endothelial cells

Biochemical Society Transactions ◽

10.1042/bst20110606 ◽

2012 ◽

Vol 40 (1) ◽

pp. 1-5 ◽

Cited By ~ 9

Author(s):

Gillian R. Milne ◽

Timothy M. Palmer ◽

Stephen J. Yarwood

Keyword(s):

Endothelial Cells ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Vascular Endothelial Cells ◽

Inflammatory Diseases ◽

Circulatory System ◽

Vascular Endothelial ◽

Protective Mechanisms ◽

Enhancer Binding Protein ◽

Developed World

Chronic inflammatory diseases, such as atherosclerosis, are a major cause of death and disability in the developed world. In this respect, although cholesterol obviously plays a predominant role in atherosclerosis, targeting inflammation at lesion sites may be just as important. Indeed, elevated IL-6 (interleukin 6) levels are as strongly associated with coronary heart disease as increased cholesterol. We have been investigating novel cAMP-regulated pathways that combat the action of pro-inflammatory cytokines, such as IL-6 and leptin, in the VECs (vascular endothelial cells) of the circulatory system. In this respect, we have begun to unravel new molecular mechanisms by which the cAMP/Epac1 (exchange protein directly activated by cAMP 1)/Rap1 pathway can initiate a rigorous programme of protective anti-inflammatory responses in VECs. Central to this is the coupling of cAMP elevation to the mobilization of two C/EBP (CCAAT/enhancer-binding protein) family transcription factors, resulting in the induction of the SOCS3 (suppressor of cytokine signalling 3) gene, which attenuates pro-inflammatory cytokine signalling in VECs. These novel ‘protective’ mechanisms of cAMP action will inform the development of the next generation of pharmaceuticals specifically designed to combat endothelial inflammation associated with cardiovascular disease.

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The Serum IL-6 Profile and Treg/Th17 Peripheral Cell Populations in Patients with Type 1 Diabetes

Mediators of Inflammation ◽

10.1155/2013/205284 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 25

Author(s):

Monika Ryba-Stanisławowska ◽

Maria Skrzypkowska ◽

Jolanta Myśliwska ◽

Małgorzata Myśliwiec

Keyword(s):

Immune Response ◽

Type 1 Diabetes ◽

Quantitative Analysis ◽

Inflammatory Diseases ◽

T Cell Subsets ◽

Cell Populations ◽

Peripheral Cell ◽

Chronic Inflammatory Diseases ◽

Cell Balance

IL-6 is a pleiotropic cytokine involved in the regulation of the immune response, inflammation, and hematopoeisis. Its elevated levels are found in a range of autoimmune and chronic inflammatory diseases. IL-6 is also involved in regulation of the balance between two T cell subsets: Tregs and Th17, which have contradictory functions in the control of inflammation. The present study provides a quantitative analysis regarding the Th17/Treg cell balance in peripheral blood of children with type 1 diabetes and its association with serum IL-6 level.

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An Important Role of Blood and Lymphatic Vessels in Inflammation and Allergy

Journal of Allergy ◽

10.1155/2013/672381 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 28

Author(s):

Silvana Zgraggen ◽

Alexandra M. Ochsenbein ◽

Michael Detmar

Keyword(s):

Inflammatory Responses ◽

Inflammatory Diseases ◽

Experimental Studies ◽

Lymphatic Vessels ◽

Allergic Inflammation ◽

Skin Inflammation ◽

Chronic Inflammatory Diseases ◽

Chronic Skin ◽

Targeted Inhibition ◽

Endothelial Growth Factor

Angiogenesis and lymphangiogenesis, the growth of new vessels from preexisting ones, have received increasing interest due to their role in tumor growth and metastatic spread. However, vascular remodeling, associated with vascular hyperpermeability, is also a key feature of many chronic inflammatory diseases including asthma, atopic dermatitis, psoriasis, and rheumatoid arthritis. The major drivers of angiogenesis and lymphangiogenesis are vascular endothelial growth factor- (VEGF-)A and VEGF-C, activating specific VEGF receptors on the lymphatic and blood vascular endothelium. Recent experimental studies found potent anti-inflammatory responses after targeted inhibition of activated blood vessels in models of chronic inflammatory diseases. Importantly, our recent results indicate that specific activation of lymphatic vessels reduces both acute and chronic skin inflammation. Thus, antiangiogenic and prolymphangiogenic therapies might represent a new approach to treat chronic inflammatory disorders, including those due to chronic allergic inflammation.

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How fragile we are. Influence of STimulator of INterferon Genes, STING, variants on pathogen recognition and immune response efficiency

10.1101/2021.07.12.452045 ◽

2021 ◽

Author(s):

Jeremy Morere ◽

Cecilia Hognon ◽

Tom Miclot ◽

Tao Jiang ◽

Elise Dumont ◽

...

Keyword(s):

Immune Response ◽

Molecular Mechanisms ◽

Viral Infections ◽

Inflammatory Diseases ◽

Dynamical Behavior ◽

Structural Features ◽

Type I Interferons ◽

Machine Learning Techniques ◽

Type I ◽

Interaction Patterns

The STimulator of INterferon Genes (STING) protein is a cornerstone of the human immune response. Its activation by cGAMP upon the presence of cytosolic DNA stimulates the production of type I interferons and inflammatory cytokines which are crucial for protecting cells from infections. STING signaling pathway can also influence both tumor-suppressive and tumor-promoting mechanisms, rendering it an appealing target for drug design. In the human population, several STING variants exist and exhibit dramatic differences in their activity, impacting the efficiency of the host defense against infections. Understanding the differential molecular mechanisms exhibited by these variants is of utmost importance notably towards personalized medicine treatments against diseases such as viral infections (COVID-19, Dengue...), cancers, or auto-inflammatory diseases. Owing to micro-seconds scale molecular modeling simulations and post-processing by contacts analysis and Machine Learning techniques, we reveal the dynamical behavior of four STING variants (wild type, G230A, R293Q, and G230A-R293Q) and we rationalize the variability of efficiency observed experimentally. Our results show that the decrease of STING activity is linked to a stiffening of key-structural features of the binding cavity, together with changes of the interaction patterns within the protein.

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Modeling Inflammation in Zebrafish for the Development of Anti-inflammatory Drugs

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.620984 ◽

2021 ◽

Vol 8 ◽

Author(s):

Yufei Xie ◽

Annemarie H. Meijer ◽

Marcel J. M. Schaaf

Keyword(s):

Immune System ◽

Inflammatory Response ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Critical Role ◽

Model Systems ◽

Trinitrobenzene Sulfonic Acid ◽

Inflammatory Drugs ◽

Anti Inflammatory

Dysregulation of the inflammatory response in humans can lead to various inflammatory diseases, like asthma and rheumatoid arthritis. The innate branch of the immune system, including macrophage and neutrophil functions, plays a critical role in all inflammatory diseases. This part of the immune system is well-conserved between humans and the zebrafish, which has emerged as a powerful animal model for inflammation, because it offers the possibility to image and study inflammatory responses in vivo at the early life stages. This review focuses on different inflammation models established in zebrafish, and how they are being used for the development of novel anti-inflammatory drugs. The most commonly used model is the tail fin amputation model, in which part of the tail fin of a zebrafish larva is clipped. This model has been used to study fundamental aspects of the inflammatory response, like the role of specific signaling pathways, the migration of leukocytes, and the interaction between different immune cells, and has also been used to screen libraries of natural compounds, approved drugs, and well-characterized pathway inhibitors. In other models the inflammation is induced by chemical treatment, such as lipopolysaccharide (LPS), leukotriene B4 (LTB4), and copper, and some chemical-induced models, such as treatment with trinitrobenzene sulfonic acid (TNBS), specifically model inflammation in the gastro-intestinal tract. Two mutant zebrafish lines, carrying a mutation in the hepatocyte growth factor activator inhibitor 1a gene (hai1a) and the cdp-diacylglycerolinositol 3-phosphatidyltransferase (cdipt) gene, show an inflammatory phenotype, and they provide interesting model systems for studying inflammation. These zebrafish inflammation models are often used to study the anti-inflammatory effects of glucocorticoids, to increase our understanding of the mechanism of action of this class of drugs and to develop novel glucocorticoid drugs. In this review, an overview is provided of the available inflammation models in zebrafish, and how they are used to unravel molecular mechanisms underlying the inflammatory response and to screen for novel anti-inflammatory drugs.

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