Macrophage Polarization in Chronic Inflammatory Diseases: Killers or Builders?

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.

Download Full-text

Taenia crassiceps-Excreted/Secreted Products Induce a Defined MicroRNA Profile that Modulates Inflammatory Properties of Macrophages

Journal of Immunology Research ◽

10.1155/2019/2946713 ◽

2019 ◽

Vol 2019 ◽

pp. 1-24 ◽

Cited By ~ 2

Author(s):

Diana Martínez-Saucedo ◽

Juan de Dios Ruíz-Rosado ◽

César Terrazas ◽

Blanca E. Callejas ◽

Abhay R. Satoskar ◽

...

Keyword(s):

Molecular Mechanisms ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Macrophage Polarization ◽

Helminth Parasites ◽

Chronic Infections ◽

Taenia Crassiceps ◽

Microrna Profile ◽

Proinflammatory Responses

Helminth parasites modulate immune responses in their host to prevent their elimination and to establish chronic infections. Our previous studies indicate that Taenia crassiceps-excreted/secreted antigens (TcES) downregulate inflammatory responses in rodent models of autoimmune diseases, by promoting the generation of alternatively activated-like macrophages (M2) in vivo. However, the molecular mechanisms triggered by TcES that modulate macrophage polarization and inflammatory response remain unclear. Here, we found that, while TcES reduced the production of inflammatory cytokines (IL-6, IL-12, and TNFα), they increased the release of IL-10 in LPS-induced bone marrow-derived macrophages (BMDM). However, TcES alone or in combination with LPS or IL-4 failed to increase the production of the canonical M1 or M2 markers in BMDM. To further define the anti-inflammatory effect of TcES in the response of LPS-stimulated macrophages, we performed transcriptomic array analyses of mRNA and microRNA to evaluate their levels. Although the addition of TcES to LPS-stimulated BMDM induced modest changes in the inflammatory mRNA profile, it induced the production of mRNAs associated with the activation of different receptors, phagocytosis, and M2-like phenotype. Moreover, we found that TcES induced upregulation of specific microRNAs, including miR-125a-5p, miR-762, and miR-484, which are predicted to target canonical inflammatory molecules and pathways in LPS-induced BMDM. These results suggest that TcES can modulate proinflammatory responses in macrophages by inducing regulatory posttranscriptional mechanisms and hence reduce detrimental outcomes in hosts running with inflammatory diseases.

Download Full-text

Immunometabolic function of cholesterol in cardiovascular disease and beyond

Cardiovascular Research ◽

10.1093/cvr/cvz127 ◽

2019 ◽

Vol 115 (9) ◽

pp. 1393-1407 ◽

Cited By ~ 15

Author(s):

Laurent Yvan-Charvet ◽

Fabrizia Bonacina ◽

Rodolphe Renè Guinamard ◽

Giuseppe Danilo Norata

Keyword(s):

Immune Response ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Cholesterol Metabolism ◽

Inflammatory Diseases ◽

Inflammasome Activation ◽

Mevalonate Kinase Deficiency ◽

Cholesterol Accumulation ◽

Cellular Cholesterol ◽

Chronic Inflammatory Diseases

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.

Download Full-text

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.

Download Full-text

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.

Download Full-text

The Response of Macrophages and Neutrophils to Hypoxia in the Context of Cancer and Other Inflammatory Diseases

Mediators of Inflammation ◽

10.1155/2016/2053646 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 25

Author(s):

Antje Egners ◽

Merve Erdem ◽

Thorsten Cramer

Keyword(s):

Endothelial Cells ◽

Inflammatory Diseases ◽

Neutrophil Function ◽

Proper Function ◽

Low Oxygen ◽

Bacterial Killing ◽

Molecular Responses ◽

Chronic Inflammatory Diseases ◽

Hypoxic Conditions ◽

Cellular Components

Lack of oxygen (hypoxia) is a hallmark of a multitude of acute and chronic diseases and can be either beneficial or detrimental for organ restitution and recovery. In the context of inflammation, hypoxia is particularly important and can significantly influence the course of inflammatory diseases. Macrophages and neutrophils, the chief cellular components of innate immunity, display distinct properties when exposed to hypoxic conditions. Virtually every aspect of macrophage and neutrophil function is affected by hypoxia, amongst others, morphology, migration, chemotaxis, adherence to endothelial cells, bacterial killing, differentiation/polarization, and protumorigenic activity. Prominent arenas of macrophage and neutrophil function, for example, acute/chronic inflammation and the microenvironment of solid tumors, are characterized by low oxygen levels, demonstrating the paramount importance of the hypoxic response for proper function of these cells. Members of the hypoxia-inducible transcription factor (HIF) family emerged as pivotal molecular regulators of macrophages and neutrophils. In this review, we will summarize the molecular responses of macrophages and neutrophils to hypoxia in the context of cancer and other chronic inflammatory diseases and discuss the potential avenues for therapeutic intervention that arise from this knowledge.

Download Full-text

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.

Download Full-text

Protective Features of Autophagy in Pulmonary Infection and Inflammatory Diseases

Cells ◽

10.3390/cells8020123 ◽

2019 ◽

Vol 8 (2) ◽

pp. 123 ◽

Cited By ~ 12

Author(s):

Kui Wang ◽

Yi Chen ◽

Pengju Zhang ◽

Ping Lin ◽

Na Xie ◽

...

Keyword(s):

Pulmonary Infection ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Autophagy Pathway ◽

Pulmonary Arterial ◽

Cellular Components ◽

Cellular Stressors

Autophagy is a highly conserved catabolic process involving autolysosomal degradation of cellular components, including protein aggregates, damaged organelles (such as mitochondria, endoplasmic reticulum, and others), as well as various pathogens. Thus, the autophagy pathway represents a major adaptive response for the maintenance of cellular and tissue homeostasis in response to numerous cellular stressors. A growing body of evidence suggests that autophagy is closely associated with diverse human diseases. Specifically, acute lung injury (ALI) and inflammatory responses caused by bacterial infection or xenobiotic inhalation (e.g., chlorine and cigarette smoke) have been reported to involve a spectrum of alterations in autophagy phenotypes. The role of autophagy in pulmonary infection and inflammatory diseases could be protective or harmful dependent on the conditions. In this review, we describe recent advances regarding the protective features of autophagy in pulmonary diseases, with a focus on ALI, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), tuberculosis, pulmonary arterial hypertension (PAH) and cystic fibrosis.

Download Full-text

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.

Download Full-text

Regulation of Notch 1 signaling in THP-1 cells enhances M2 macrophage differentiation

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00896.2013 ◽

2014 ◽

Vol 307 (11) ◽

pp. H1634-H1642 ◽

Cited By ~ 24

Author(s):

Reetu D. Singla ◽

Jing Wang ◽

Dinender K. Singla

Keyword(s):

Notch Signaling ◽

Proinflammatory Cytokine ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Macrophage Polarization ◽

Cellular Stress ◽

Culture Conditions ◽

M2 Macrophage ◽

Macrophage Differentiation ◽

Anti Inflammatory

Macrophage polarization is emerging as an important area of research for the development of novel therapeutics to treat inflammatory diseases. Within the current study, the role of Notch1R in macrophage differentiation was investigated as well as downstream effects in THP-1 monocytes cultured in “inflammation mimicry” media. Interference of Notch signaling was achieved using either the pharmaceutical inhibitor DAPT or Notch1R small interfering RNA (siRNA), and Notch1R expression, macrophage phenotypes, and anti- and proinflammatory cytokine expression were evaluated. Data presented show that Notch1R expression on M1 macrophages as well as M1 macrophage differentiation is significantly elevated during cellular stress ( P < 0.05). However, under identical culture conditions, interference to Notch signaling via Notch1R inhibition mitigated these results as well as promoted M2 macrophage differentiation. Moreover, when subjected to cellular stress, macrophage secretion of proinflammatory cytokines was significantly heightened ( P < 0.05). Importantly, Notch1R inhibition not only diminished proinflammatory cytokine secretion but also enhanced anti-inflammatory protein release ( P < 0.05). Our data suggest that Notch1R plays a pivotal role in M1 macrophage differentiation and heightened inflammatory responses. Therefore, we conclude that inhibition of Notch1R and subsequent downstream signaling enhances monocyte to M2 polarized macrophage outcomes and promotes anti-inflammatory mediation during cellular stress.

Download Full-text

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.

Download Full-text