Potential of glucocorticoids to treat intestinal inflammation during sepsis
Introduction
Glucocorticoids (GCs) are steroid hormones, produced by the adrenal gland of all vertebrate animals, and widely used in the treatment of various autoimmune, inflammatory and allergic disorders, such as rheumatoid arthritis (RA), lupus erythematosus, inflammatory bowel disease (IBD), transplant rejection and asthma [1]. They work via binding to the glucocorticoid receptor (GR), a member of the nuclear receptor family. Upon ligand binding, GR dislocates from its chaperone complex and translocates to the nucleus. In the nucleus, GR interacts with the genomic DNA or with other proteins to regulate gene transcription of thousands of genes (protein coding, micro-RNA and long non-coding genes). GR can influence gene expression via several ways, but the best known is the GR dimer mechanism, in which GR homodimers bind to glucocorticoid-responsive-elements (GREs) to activate gene transcription. GR can also transcriptionally repress genes by binding, as a monomer to other transcription factors (TFs) such as NF-kB and AP-1, thereby preventing them from activating gene transcription.
GCs are considered to be the most effective anti-inflammatory drugs. It is estimated that about 3% of the Western population are using GCs [2]. However, the therapeutic use of GCs is hampered by the occurrence of side effects such as osteoporosis, hyperglycemia, disturbed fat redisposition, muscle atrophy and hypertension, especially during chronic usage [3]. Furthermore, some patients do not respond to the therapy, a phenomenon called glucocorticoid resistance (GCR). This GCR occurs in diseases such as severe asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, inflammatory bowel disease (IBD) and sepsis. Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection [4]. The incidence of sepsis is still increasing year after year, and hence it remains one of the leading causes of death globally [5]. Unfortunately, sepsis patients only get supportive care, consisting of rapid delivery of antibiotics, fluid resuscitation, vasopressor administration, lung ventilation and nutritional support [6]. Sepsis consists of an early pro-inflammatory phase, causing early deaths. Thanks to improved clinical management, many patients survive this first phase. However, these patients can enter an immunosuppressive status in which they can die because of the inability to clear primary infections as well because of the development of secondary infections [7].
Although sepsis consists of an early pro-inflammatory phase, the systemic delivery of anti-inflammatory GCs has not really led to a breakthrough in sepsis [8,9]. However, experiments with animal models do show the importance of GCs and GR signaling during sepsis. Both injection of GR antagonist RU486 and adrenalectomy sensitize mice for tumor necrosis factor alpha (TNFα)-induced systemic inflammatory response syndrome (SIRS) [10,11]. Furthermore, mice carrying mutant GR alleles, for example, the GRdim mice which have a point-mutated GR with reduced transcriptional activity, are very sensitive in SIRS and sepsis models [12, 13, 14, 15]. Also GR signaling in T-cells, dendritic cells and macrophages has shown to be important, since mice with conditional ablation of GR in these immune cells exhibit higher mortality in different sepsis models [12,16, 17, 18, 19]. In addition, intestinal GR has shown to be important in the protection against TNFα-induced systemic inflammation [13].
These results show that there still could be a future in the use of GCs in sepsis, provided that a number of essential questions about GR in sepsis are addressed. One major question is if GCs can be made really efficient in sepsis, if we target them to the right cells. Multiple components of the host response are involved in the mortality of sepsis, but the gut is seen as the motor of sepsis and multiple organ dysfunction [20]. Since GC treatment reveals therapeutic effects in Crohn’s disease (CD) and in pre-clinical sepsis models, we hypothesize that targeting GCs to the gut or stimulating local GC production in the gut forms an interesting strategy for sepsis treatment.
Section snippets
Intestinal damage in sepsis
The gastrointestinal tract is composed of the mouth, the esophagus, the stomach, the small intestine (subdivided into duodenum, jejunum and ileum) and the large intestine (subdivided into cecum, colon, rectum and anal canal). The inner layer of the intestine consists of IECs and separates the underlying tissue from the external environment. The IECs absorb nutrients from the food and interact with the microbiome and yet exclude pathogens, toxins and allergens. When this process is impeded,
Glucocorticoids in the treatment of sepsis to ameliorate gut damage
Currently, no therapy exists that targets the gut epithelium, hyperpermeability or mucus in sepsis patients. However, pre-clinical sepsis studies show interesting interventions aimed at restoring the intestinal barrier. These studies are associated with improvements in survival in animal models of critical illness [33,34]. Administration of systemic epidermal growth factor (EGF) after the onset of the infection decreased mortality in pneumonia-induced and polymicrobial-induced sepsis mouse
Looking for a ‘next generation’ glucocorticoid therapy?
Systemic delivery of GCs has not really led to a breakthrough in sepsis [43, 44, 45]. There may be many reasons behind this observation. But because of the previous paragraphs, according to us, it would make sense (1) to generate GCs that stimulate maximal GR dimerization and (2) to address these GCs specifically to the IECs. An old dogma states that the side effects of GC therapy are due to GR dimer activated genes playing a role in glucose synthesis and fat metabolism. The anti-inflammatory
Conclusions
Despite increasing knowledge about the molecular mechanisms in the pathogenesis of sepsis, current treatments are mainly limited to antibiotic treatment and support of vital functions. Even GCs, the most potent anti-inflammatory drugs, have not led to major therapeutic advances. The gut has been hypothesized as the ‘motor’ in sepsis, as the gut integrity and intestinal homeostasis are critically affected in sepsis and this leads to both local as distant damage, resulting in multiple organ
Conflicts of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
CRediT authorship contribution statement
Kelly Van Looveren: Writing - original draft, Writing - review & editing. Charlotte Wallaeys: Writing - original draft, Writing - review & editing. Claude Libert: Writing - original draft, Writing - review & editing.
References (65)
- et al.
Mechanisms involved in the side effects of glucocorticoids
Pharmacol Ther
(2002) - et al.
Tumor necrosis factor inhibits glucocorticoid receptor function in mice: a strong signal toward lethal shock
J Biol Chem
(2011) - et al.
Macrophage glucocorticoid receptors regulate Toll-like receptor 4-mediated inflammatory responses by selective inhibition of p38 MAP kinase
Blood
(2007) - et al.
The gut as the motor of multiple organ dysfunction in critical illness
Crit Care Clin
(2016) - et al.
Myosin light chain kinase is involved in lipopolysaccharide-induced disruption of colonic epithelial barrier and bacterial translocation in rats
Am J Pathol
(2005) Gut-origin sepsis: evolution of a concept
Surgeon
(2012)- et al.
TNFR1-induced lethal inflammation is mediated by goblet and Paneth cell dysfunction
Mucosal Immunol
(2015) - et al.
Interleukin 28 is a potential therapeutic target for sepsis
Clin Immunol
(2019) - et al.
A screening assay for Selective Dimerizing Glucocorticoid Receptor Agonists and Modulators (SEDIGRAM) that are effective against acute inflammation
Sci Rep
(2018) - et al.
Budesonide-loaded nanostructured lipid carriers reduce inflammation in murine DSS-induced colitis
Int J Pharm
(2013)
Solid lipid nanoparticles delivering anti-inflammatory drugs to treat inflammatory bowel disease: effects in an in vivo model
World J Gastroenterol
Intestinal glucocorticoid synthesis enzymes in pediatric inflammatory bowel disease patients
Genes Immun
Antiinflammatory action of glucocorticoids—new mechanisms for old drugs
N Engl J Med
The epidemiology of glucocorticoid-associated adverse events
Curr Opin Rheumatol
The third international consensus definitions for sepsis and septic shock (sepsis-3)
JAMA J Am Med Assoc
Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations
Am J Respir Crit Care Med
Surviving sepsis campaign: research priorities for sepsis and septic shock
Intensive Care Med
Immunosuppression in patients who die of sepsis and multiple organ failure
JAMA
Corticosteroids in sepsis: from bench to bedside?
Shock
Corticosteroids in septic shock: a systematic review and network meta-analysis
Crit Care
The glucocorticoid antagonist RU38486 mimics interleukin‐1 in its sensitization to the lethal and interleukin‐6‐inducing properties of tumor necrosis factor
Eur J Immunol
Glucocorticoid receptor dimerization is required for survival in septic shock via suppression of interleukin-1 in macrophages
FASEB J
Glucocorticoid receptor dimers control intestinal STAT1 and TNF-induced inflammation in mice
J Clin Invest
Glucocorticoid receptor dimerization induces MKP1 to protect against TNF-induced inflammation
J Clin Invest
Glucocorticoid receptor dimerization is required for proper recovery of LPS-induced inflammation, sickness behavior and metabolism in mice
Mol Psychiatry
Scavenger receptor BI and high-density lipoprotein regulate thymocyte apoptosis in sepsis
Arterioscler Thromb Vasc Biol
Fighting the fire: mechanisms of inflammatory gene regulation by the glucocorticoid receptor
Front Immunol
Suppression of dendritic cell-derived IL-12 by endogenous glucocorticoids is protective in LPS-induced sepsis
PLoS Biol
Paneth cells in intestinal physiology and pathophysiology
World J Gastrointest Pathophysiol
Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts
Nature
The Peyer’s patch mononuclear phagocyte system at steady state and during infection
Front Immunol
Intestinal goblet cells and mucins in health and disease: recent insights and progress
Curr Gastroenterol Rep
Cited by (6)
Protective effect of isosteviol sodium against LPS-induced multiple organ injury by regulating of glycerophospholipid metabolism and reducing macrophage-driven inflammation
2021, Pharmacological ResearchCitation Excerpt :Importantly, in terms of clinical aspects, SIRS is a disease with an extremely high mortality rate, especially in patients who underwent major surgery [4]. Despite glucocorticosteroids remain the most effective treatment for inflammatory diseases, their side effects lend limitations to their clinical utility [37]. High-dose corticosteroid treatment for sepsis has become a controversial clinical issue, as patients with early and severe SIRS failed to benefit from high-dose corticosteroid treatment [38,39], which was in line with our study showing that Dex failed to show a therapeutic effect on MOI in septic mice and even had a potentially harmful effect in terms of an exuberant inflammatory response.
Editorial overview: Immunomodulation 2020 – nuclear receptors
2020, Current Opinion in PharmacologyImpact of Glucocorticoids on Cardiovascular System—The Yin Yang Effect
2022, Journal of Personalized MedicineIntestinal Epithelial Cell Exosome Launches IL-1β-Mediated Neuron Injury in Sepsis-Associated Encephalopathy
2022, Frontiers in Cellular and Infection MicrobiologyPresent and Future Therapeutic Approaches to Barrier Dysfunction
2021, Frontiers in NutritionGhrelin Alleviates Intestinal Dysfunction in Sepsis Through the KLF4/MMP2 Regulatory Axis by Activating SIRT1
2021, Frontiers in Immunology
- 3
Share first authorship.