Potential of glucocorticoids to treat intestinal inflammation during sepsis

Glucocorticoids (GCs) are steroid hormones characterized by their anti-inflammatory and immunosuppressive nature. Although GCs are very commonly prescribed, in several diseases, including sepsis, their clinical treatment is hampered by side effects and by the occurrence of glucocorticoid resistance (GCR). Sepsis is defined as a life-threatening organ dysfunction, initiated by a dysregulated systemic host response to infections. With at least 19 million cases per year and a lethality rate of about 25%, sepsis is one of the most urgent unmet medical needs. The gut is critically affected during sepsis and is considered as a driving force in this disease. Despite there is no effective treatment for sepsis, pre-clinical studies show promising results by preserving or restoring gut integrity. 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. According to recent findings that show that dimerization of the glucocorticoid receptor (GR) is essential in inducing anti-inflammatory effects in pre-clinical sepsis models, we predict that new generation GCs that selectively dimerize the GR, can therefore positively affect the outcome of sepsis treatment.

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 GR^dim 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.