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Special Issue "Inflammatory/Immune Modulations by Old and New Glucocorticoids: From Cell to Medical Application"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (23 October 2018).

Special Issue Editor

Guest Editor
Assoc. Prof. Dr. Giuseppe Nocentini Website E-Mail
Department of Medicine, University of Perugia, 06129 Perugia, Italy
Phone: +39 0755858186
Interests: Immunopharmacology; T lymphocyte co-stimulation; Regulatory T cell (Treg) modulation; Glucocorticoids; Immune checkpoint inhibitors; Cell therapy; Autoimmune diseases; Immuno-oncology

Special Issue Information

Dear Colleagues,

Despite their venerable age, glucocorticoids still challenge and surprise us. Their widespread use in clinical practice and their surprisingly tissue-specific actions in maintaining body homeostasis demand further studies to fully decipher their mechanisms of action. If we only consider the genomic and non-genomic effects of glucocorticoids, the long- and short-term effects of synthetic glucocorticoids, the opposite effects exerted on multiple types of immune cells, and their crucial roles in differentiation, apoptosis, and proliferation, we realize important questions remain to be addressed. In particular, the cross-talk between activated glucocorticoid receptor (GR) and GR interactome with other receptors and signaling molecules appears a field of undisclosed potentials.

At the cellular levels, some evidence suggests that glucocorticoids modulate differentiation and survival of regulatory T cells (Tregs) and tolerogenic macrophages (e.g., M2), possibly by shaping the long-term maturation of the immune system. These effects may have a favorable impact on the development of inflammatory and autoimmune diseases but, at the same time, a deleterious effect on cancer immunosurveillance and progression. Hence, the interactions between synthetic glucocorticoids and immunosuppressive/immunomodulatory biologics that are currently in use or still under investigation (e.g., anti-CD3 and IL-2 antibodies), as well as synthetic glucocorticoids and epigenetic drugs (e.g., histone deacetylase inhibitors), deserve to be investigated.

The growing awareness concerning the effects of glucocorticoids on neuroendocrine system and behavior has created an urgent need to investigate the glucocorticoid-dependent neural network shaping. The concern about the sexually dimorphic actions of glucocorticoids on neuroendocrine system and other tissues has been catching on from a theoretic point of view and soon will have an impact on the clinics. The glucocorticoid-dependent damage to the skin and the direct protection of numerous non-immune cell types from the deleterious effect of inflammation are well known, but the underlined mechanisms deserve more studies. Topical glucocorticoids, including inhalation corticosteroids (ICSs), play a crucial role in the treatment of asthma, inflammatory bowel disease (IBD) and skin diseases, but their mechanism of action and adverse effects are still under investigation. Finally, new molecules modulating the activity of GR or mimicking the effect of GR activation are investigated with interesting results.

My hope and my ambition are that this Special Issue of IJMS may summarize these issues and shed new light on some of these, thanks to the contribution and the outstanding scientific research of the best scientists working in the glucocorticoid field.

Assoc. Prof. Dr. Giuseppe Nocentini
Guest Editor

Manuscript Submission Information

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Keywords

  • Genomic effects of glucocorticoids
  • Non-genomic effects of glucocorticoids
  • Glucocorticoid-dependent modulation of the immune cells
  • Effects of glucocorticoids on differentiation and survival of Treg cells
  • Effects of glucocorticoids on differentiation and survival of tolerogenic macrophages
  • Glucocorticoid-dependent survival of parenchymal cells
  • Effects of glucocorticoids on neurons
  • New drugs binding to the glucocorticoid receptor
  • Topical steroids in asthma and inflammatory bowel disease
  • Combination therapy glucocorticoids/biologics
  • Sexually dimorphic effects of glucocorticoids
  • Adverse effects of topical steroids

Published Papers (10 papers)

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Research

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Open AccessArticle
CB2 Receptor Stimulation and Dexamethasone Restore the Anti-Inflammatory and Immune-Regulatory Properties of Mesenchymal Stromal Cells of Children with Immune Thrombocytopenia
Int. J. Mol. Sci. 2019, 20(5), 1049; https://doi.org/10.3390/ijms20051049 - 28 Feb 2019
Abstract
Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by antibody-mediated platelet destruction, with a complex and unclear pathogenesis. The impaired immunosuppressive capacity of mesenchymal stromal cells in ITP patients (ITP-MSCs) might play a role in the development of the disease. Correcting the MSC [...] Read more.
Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by antibody-mediated platelet destruction, with a complex and unclear pathogenesis. The impaired immunosuppressive capacity of mesenchymal stromal cells in ITP patients (ITP-MSCs) might play a role in the development of the disease. Correcting the MSC defects could represent an alternative therapeutic approach for ITP. High-dose dexamethasone (HD-Dexa) is the mainstay of the ITP therapeutic regimen, although it has several side effects. We previously demonstrated a role for cannabinoid receptor 2 (CB2) as a mediator of anti-inflammatory and immunoregulatory properties of human MSCs. We analyzed the effects of CB2 stimulation, with the selective agonist JWH-133, and of Dexa alone and in combination on ITP-MSC survival and immunosuppressive capacity. We provided new insights into the pathogenesis of ITP, suggesting CB2 receptor involvement in the impairment of ITP-MSC function and confirming MSCs as responsive cellular targets of Dexa. Moreover, we demonstrated that CB2 stimulation and Dexa attenuate apoptosis, via Bcl2 signaling, and restore the immune-modulatory properties of MSCs derived from ITP patients. These data suggest the possibility of using Dexa in combination with JWH-133 in ITP, reducing its dose and side effects but maintaining its therapeutic benefits. Full article
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Open AccessArticle
Potential Dissociative Glucocorticoid Receptor Activity for Protopanaxadiol and Protopanaxatriol
Int. J. Mol. Sci. 2019, 20(1), 94; https://doi.org/10.3390/ijms20010094 - 27 Dec 2018
Abstract
Glucocorticoids are steroid hormones that regulate inflammation, growth, metabolism, and apoptosis via their cognate receptor, the glucocorticoid receptor (GR). GR, acting mainly as a transcription factor, activates or represses the expression of a large number of target genes, among them, many genes of [...] Read more.
Glucocorticoids are steroid hormones that regulate inflammation, growth, metabolism, and apoptosis via their cognate receptor, the glucocorticoid receptor (GR). GR, acting mainly as a transcription factor, activates or represses the expression of a large number of target genes, among them, many genes of anti-inflammatory and pro-inflammatory molecules, respectively. Transrepression activity of glucocorticoids also accounts for their anti-inflammatory activity, rendering them the most widely prescribed drug in medicine. However, chronic and high-dose use of glucocorticoids is accompanied with many undesirable side effects, attributed predominantly to GR transactivation activity. Thus, there is a high need for selective GR agonist, capable of dissociating transrepression from transactivation activity. Protopanaxadiol and protopanaxatriol are triterpenoids that share structural and functional similarities with glucocorticoids. The molecular mechanism of their actions is unclear. In this study applying induced-fit docking analysis, luciferase assay, immunofluorescence, and Western blot analysis, we showed that protopanaxadiol and more effectively protopanaxatriol are capable of binding to GR to activate its nuclear translocation, and to suppress the nuclear factor-kappa beta activity in GR-positive HeLa and HEK293 cells, but not in GR-low level COS-7 cells. Interestingly, no transactivation activity was observed, whereas suppression of the dexamethasone-induced transactivation of GR and induction of apoptosis in HeLa and HepG2 cells were observed. Thus, our results indicate that protopanaxadiol and protopanaxatriol could be considered as potent and selective GR agonist. Full article
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Open AccessArticle
Cigarette Smoke During Breastfeeding in Rats Changes Glucocorticoid and Vitamin D Status in Obese Adult Offspring
Int. J. Mol. Sci. 2018, 19(10), 3084; https://doi.org/10.3390/ijms19103084 - 09 Oct 2018
Cited by 2
Abstract
Maternal smoking increases obesogenesis in the progeny. Obesity is associated with several hormonal dysfunctions. In a rat model of postnatal tobacco smoke exposure, we previously reported increased central fat depot and disruption of some hormonal systems in the adult offspring. As both glucocorticoids [...] Read more.
Maternal smoking increases obesogenesis in the progeny. Obesity is associated with several hormonal dysfunctions. In a rat model of postnatal tobacco smoke exposure, we previously reported increased central fat depot and disruption of some hormonal systems in the adult offspring. As both glucocorticoids and vitamin D alter lipogenesis and adipogenesis, here we evaluated the metabolism of these two hormones in visceral adipose tissue (VAT) and liver by Western blotting, and possible associations with lipogenesis biomarkers in adult rats that were exposed to tobacco smoke during their suckling period. At postnatal day (PN) 3, dams and offspring of both sexes were exposed (S group) or not (C group) to tobacco smoke, 4 × 1 h/day. At PN180, corticosteronemia was lower in S male and higher in S female offspring, without alterations in peripheral glucocorticoid metabolism and receptor. Adrenal ACTH receptor (MC2R) was higher in both sexes of S group. Despite unchanged serum vitamin D, liver 25-hydroxylase was higher in both sexes of S group. Male S offspring had higher 1α-hydroxylase, acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS) in VAT. Both sexes showed increased ACC protein content and reduced sirtuin mRNA in liver. Male S offspring had lower liver peroxisome proliferator-activated receptor-α. Tobacco exposure during lactation induced abdominal obesity in both sexes via distinct mechanisms. Males and females seem to develop HPA-axis dysfunction instead of changes in glucocorticoid metabolism and action. Lipogenesis in VAT and liver, as well as vitamin D status, are more influenced by postnatal smoke exposure in male than in female adult rat offspring. Full article
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Open AccessArticle
Blood Pressure Profile and N-Terminal-proBNP Dynamics in Response to Intravenous Methylprednisolone Pulse Therapy of Severe Graves’ Orbitopathy
Int. J. Mol. Sci. 2018, 19(10), 2918; https://doi.org/10.3390/ijms19102918 - 26 Sep 2018
Cited by 1
Abstract
Hypercortisolemia is associated with increased risk of hypertension. Natural and synthetic glucocorticoids (GCs) have different effects on blood pressure (BP). The effect of synthetic GCs on BP depends on the dose, treatment duration, type of GCs, and route of administration. Intravenous methylprednisolone (IVMP) [...] Read more.
Hypercortisolemia is associated with increased risk of hypertension. Natural and synthetic glucocorticoids (GCs) have different effects on blood pressure (BP). The effect of synthetic GCs on BP depends on the dose, treatment duration, type of GCs, and route of administration. Intravenous methylprednisolone (IVMP) pulse therapy is the first line of treatment for severe Graves’ orbitopathy (GO). The aim of this study was to evaluate influence of IVMP pulses on BP and N-terminal pro-brain natriuretic peptide (NT-proBNP) dynamics. A total of 32 patients with GO were treated with one IVMP pulse every week for 12 weeks. We performed 48-h BP monitoring (24-h before and 24-h after IVMP) and measured NT-proBNP before, 24 h, and 48 h after the 1st, 6th, and 12th IVMP pulse. Mean BP did not change after any of the pulses. We did not observe an increase in maximal systolic BP or mean nocturnal BP, except after the last pulse. Additionally, the dipping phenomenon was less frequent after the last pulse. We found a significant increase in median NT-proBNP levels after all analyzed pulses. Our study suggests that IVMP may have an unfavorable cumulative effect on BP. Variation in NT-proBNP concentration indicates a compensatory effect of brain natriuretic peptide secretion. Full article
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Open AccessArticle
Repression of the Glucocorticoid Receptor Aggravates Acute Ischemic Brain Injuries in Adult Mice
Int. J. Mol. Sci. 2018, 19(8), 2428; https://doi.org/10.3390/ijms19082428 - 17 Aug 2018
Cited by 2
Abstract
Strokes are one of the leading causes of mortality and chronic morbidity in the world, yet with only limited successful interventions available at present. Our previous studies revealed the potential role of the glucocorticoid receptor (GR) in the pathogenesis of neonatal hypoxic-ischemic encephalopathy [...] Read more.
Strokes are one of the leading causes of mortality and chronic morbidity in the world, yet with only limited successful interventions available at present. Our previous studies revealed the potential role of the glucocorticoid receptor (GR) in the pathogenesis of neonatal hypoxic-ischemic encephalopathy (HIE). In the present study, we investigate the effect of GR knockdown on acute ischemic brain injuries in a model of focal cerebral ischemia induced by middle cerebral artery occlusion (MCAO) in adult male CD1 mice. GR siRNAs and the negative control were administered via intracerebroventricular (i.c.v.) injection 48 h prior to MCAO. The cerebral infarction volume and neurobehavioral deficits were determined 48 h after MCAO. RT-qPCR was employed to assess the inflammation-related gene expression profiles in the brain before and after MCAO. Western Blotting was used to evaluate the expression levels of GR, the mineralocorticoid receptor (MR) and the brain-derived neurotrophic factor/tropomyosin receptor kinase B (BDNF/TrkB) signaling. The siRNAs treatment decreased GR, but not MR, protein expression, and significantly enhanced expression levels of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) in the brain. Of interest, GR knockdown suppressed BDNF/TrkB signaling in adult mice brains. Importantly, GR siRNA pretreatment significantly increased the infarction size and exacerbated the neurobehavioral deficits induced by MCAO in comparison to the control group. Thus, the present study demonstrates the important role of GR in the regulation of the inflammatory responses and neurotrophic BDNF/TrkB signaling pathway in acute ischemic brain injuries in adult mice, revealing a new insight into the pathogenesis and therapeutic potential in acute ischemic strokes. Full article
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Open AccessArticle
High-Throughput Sequencing of microRNAs in Glucocorticoid Sensitive Paediatric Inflammatory Bowel Disease Patients
Int. J. Mol. Sci. 2018, 19(5), 1399; https://doi.org/10.3390/ijms19051399 - 08 May 2018
Cited by 3
Abstract
The aim of this research was the identification of novel pharmacogenomic biomarkers for better understanding the complex gene regulation mechanisms underpinning glucocorticoid (GC) action in paediatric inflammatory bowel disease (IBD). This goal was achieved by evaluating high-throughput microRNA (miRNA) profiles during GC treatment, [...] Read more.
The aim of this research was the identification of novel pharmacogenomic biomarkers for better understanding the complex gene regulation mechanisms underpinning glucocorticoid (GC) action in paediatric inflammatory bowel disease (IBD). This goal was achieved by evaluating high-throughput microRNA (miRNA) profiles during GC treatment, integrated with the assessment of expression changes in GC receptor (GR) heterocomplex genes. Furthermore, we tested the hypothesis that differentially expressed miRNAs could be directly regulated by GCs through investigating the presence of GC responsive elements (GREs) in their gene promoters. Ten IBD paediatric patients responding to GCs were enrolled. Peripheral blood was obtained at diagnosis (T0) and after four weeks of steroid treatment (T4). MicroRNA profiles were analyzed using next generation sequencing, and selected significantly differentially expressed miRNAs were validated by quantitative reverse transcription-polymerase chain reaction. In detail, 18 miRNAs were differentially expressed from T0 to T4, 16 of which were upregulated and 2 of which were downregulated. Out of these, three miRNAs (miR-144, miR-142, and miR-96) could putatively recognize the 3’UTR of the GR gene and three miRNAs (miR-363, miR-96, miR-142) contained GREs sequences, thereby potentially enabling direct regulation by the GR. In conclusion, we identified miRNAs differently expressed during GC treatment and miRNAs which could be directly regulated by GCs in blood cells of young IBD patients. These results could represent a first step towards their translation as pharmacogenomic biomarkers. Full article
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Review

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Open AccessReview
Context-Dependent Effect of Glucocorticoids on the Proliferation, Differentiation, and Apoptosis of Regulatory T Cells: A Review of the Empirical Evidence and Clinical Applications
Int. J. Mol. Sci. 2019, 20(5), 1142; https://doi.org/10.3390/ijms20051142 - 06 Mar 2019
Cited by 1
Abstract
Glucocorticoids (GCs) are widely used to treat several diseases because of their powerful anti-inflammatory and immunomodulatory effects on immune cells and non-lymphoid tissues. The effects of GCs on T cells are the most relevant in this regard. In this review, we analyze how [...] Read more.
Glucocorticoids (GCs) are widely used to treat several diseases because of their powerful anti-inflammatory and immunomodulatory effects on immune cells and non-lymphoid tissues. The effects of GCs on T cells are the most relevant in this regard. In this review, we analyze how GCs modulate the survival, maturation, and differentiation of regulatory T (Treg) cell subsets into both murine models and humans. In this way, GCs change the Treg cell number with an impact on the mid-term and long-term efficacy of GC treatment. In vitro studies suggest that the GC-dependent expansion of Treg cells is relevant when they are activated. In agreement with this observation, the GC treatment of patients with established autoimmune, allergic, or (auto)inflammatory diseases causes an expansion of Treg cells. An exception to this appears to be the local GC treatment of psoriatic lesions. Moreover, the effects on Treg number in patients with multiple sclerosis are uncertain. The effects of GCs on Treg cell number in healthy/diseased subjects treated with or exposed to allergens/antigens appear to be context-dependent. Considering the relevance of this effect in the maturation of the immune system (tolerogenic response to antigens), the success of vaccination (including desensitization), and the tolerance to xenografts, the findings must be considered when planning GC treatment. Full article
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Open AccessReview
Clinical Use and Molecular Action of Corticosteroids in the Pediatric Age
Int. J. Mol. Sci. 2019, 20(2), 444; https://doi.org/10.3390/ijms20020444 - 21 Jan 2019
Cited by 1
Abstract
Corticosteroids are the mainstay of therapy for many pediatric disorders and sometimes are life-saving. Both endogenous and synthetic derivatives diffuse across the cell membrane and, by binding to their cognate glucocorticoid receptor, modulate a variety of physiological functions, such as glucose metabolism, immune [...] Read more.
Corticosteroids are the mainstay of therapy for many pediatric disorders and sometimes are life-saving. Both endogenous and synthetic derivatives diffuse across the cell membrane and, by binding to their cognate glucocorticoid receptor, modulate a variety of physiological functions, such as glucose metabolism, immune homeostasis, organ development, and the endocrine system. However, despite their proved and known efficacy, corticosteroids show a lot of side effects, among which growth retardation is of particular concern and specific for pediatric age. The aim of this review is to discuss the mechanism of action of corticosteroids, and how their genomic effects have both beneficial and adverse consequences. We will focus on the use of corticosteroids in different pediatric subspecialties and most common diseases, analyzing the most recent evidence. Full article
Open AccessReview
How Glucocorticoids Affect the Neutrophil Life
Int. J. Mol. Sci. 2018, 19(12), 4090; https://doi.org/10.3390/ijms19124090 - 17 Dec 2018
Cited by 2
Abstract
Glucocorticoids are hormones that regulate several functions in living organisms and synthetic glucocorticoids are the most powerful anti-inflammatory pharmacological tool that is currently available. Although glucocorticoids have an immunosuppressive effect on immune cells, they exert multiple and sometimes contradictory effects on neutrophils. From [...] Read more.
Glucocorticoids are hormones that regulate several functions in living organisms and synthetic glucocorticoids are the most powerful anti-inflammatory pharmacological tool that is currently available. Although glucocorticoids have an immunosuppressive effect on immune cells, they exert multiple and sometimes contradictory effects on neutrophils. From being extremely sensitive to the anti-inflammatory effects of glucocorticoids to resisting glucocorticoid-induced apoptosis, neutrophils are proving to be more complex than they were earlier thought to be. The aim of this review is to explain these complex pathways by which neutrophils respond to endogenous or to exogenous glucocorticoids, both under physiological and pathological conditions. Full article
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Open AccessReview
Role of Endogenous Glucocorticoids in Cancer in the Elderly
Int. J. Mol. Sci. 2018, 19(12), 3774; https://doi.org/10.3390/ijms19123774 - 27 Nov 2018
Abstract
Although not a disease itself, aging represents a risk factor for many aging-related illnesses, including cancer. Numerous causes underlie the increased incidence of malignancies in the elderly, for example, genomic instability and epigenetic alterations that occur at cellular level, which also involve the [...] Read more.
Although not a disease itself, aging represents a risk factor for many aging-related illnesses, including cancer. Numerous causes underlie the increased incidence of malignancies in the elderly, for example, genomic instability and epigenetic alterations that occur at cellular level, which also involve the immune cells. The progressive decline of the immune system functions that occurs in aging defines immunosenescence, and includes both innate and adaptive immunity; the latter undergoes major alterations. Aging and chronic stress share the abnormal hypothalamic–pituitary–adrenal axis activation, where altered peripheral glucocorticoids (GC) levels and chronic stress have been associated with accelerated cellular aging, premature immunosenescence, and aging-related diseases. Consequently, changes in GC levels and sensitivity contribute to the signs of immunosenescence, namely fewer naïve T cells, poor immune response to new antigens, decreased cell-mediated immunity, and thymic involution. GC signaling alterations also involve epigenetic alterations in DNA methylation, with transcription modifications that may contribute to immunosenescence. Immune cell aging leads to decreased levels of immunosurveillance, thereby providing tumor cells one more route for immune system escape. Here, the contribution of GC secretion and signaling dysregulation to the increased incidence of tumorigenesis in the elderly is reviewed. Full article
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