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Glucocorticoids (GCs) are steroid hormones widely used for the treatment of inflammation, autoimmune diseases, and cancer. To exert their broad physiological and therapeutic effects, GCs bind to the GC receptor (GR) which belongs to the nuclear receptor superfamily of transcription factors. Despite their success, GCs are hindered by the occurrence of side effects and glucocorticoid resistance (GCR). Increased knowledge on GC and GR biology together with a better understanding of the molecular mechanisms underlying the GC side effects and GCR are necessary for improved GC therapy development. We here provide a general overview on the current insights in GC biology with a focus on GC synthesis, regulation and physiology, role in inflammation inhibition, and on GR function and plasticity. Furthermore, novel and selective therapeutic strategies are proposed based on recently recognized distinct molecular mechanisms of the GR. We will explain the SEDIGRAM concept, which was launched based on our research results.

Sepsis is a highly lethal syndrome resulting from dysregulated immune and metabolic responses to infection, thereby compromising host homeostasis. Activation of the hypothalamic-pituitary-adrenal (HPA) axis and subsequently adrenocortical glucocorticoid (GC) production during sepsis are important regulatory processes to maintain homeostasis. Multiple preclinical studies have proven the pivotal role of endogenous GCs in tolerance against sepsis by counteracting several of the sepsis characteristics, such as excessive inflammation, vascular defects, and hypoglycemia. Sepsis is however often complicated by dysfunction of the HPA axis, resulting from critical-illness-related corticosteroid insufficiency (CIRCI) and GC resistance. Therefore, GCs have been tested as an adjunctive therapy in sepsis and septic shock in different randomized clinical trials (RCTs). Nonetheless, these studies produced conflicting results. Interestingly, adding vitamin C and thiamin to GC therapy enhances the effects of GCs, probably by reducing GC resistance, and this results in an impressive reduction in sepsis mortality as was shown in two recent preliminary retrospective before-after studies. Multiple RCTs are currently underway to validate this new combination therapy in sepsis.

Sepsis is a highly lethal and urgent unmet medical need. It is the result of a complex interplay of several pathways, including inflammation, immune activation, hypoxia, and metabolic reprogramming. Specifically, the regulation and the impact of the latter have become better understood in which the highly catabolic status during sepsis and its similarity with starvation responses appear to be essential in the poor prognosis in sepsis. It seems logical that new interventions based on the recognition of new therapeutic targets in the key metabolic pathways should be developed and may have a good chance to penetrate to the bedside. In this review, we concentrate on the pathological changes in metabolism, observed during sepsis, and the presumed underlying mechanisms, with a focus on the level of the organism and the interplay between different organ systems. Graphical Abstract In this review, Van Wingene, Vandewalle and Libert concentrate on the pathological changes in metabolism observed during sepsis, and the presumed underlying mechanisms.

Paneth cells are versatile secretory cells located in the crypts of Lieberkühn of the small intestine. In normal conditions, they function as the cornerstones of intestinal health by preserving homeostasis. They perform this function by providing niche factors to the intestinal stem cell compartment, regulating the composition of the microbiome through the production and secretion of antimicrobial peptides, performing phagocytosis and efferocytosis, taking up heavy metals, and preserving barrier integrity. Disturbances in one or more of these functions can lead to intestinal as well as systemic inflammatory and infectious diseases. This review discusses the multiple functions of Paneth cells, and the mechanisms and consequences of Paneth cell dysfunction. It also provides an overview of the tools available for studying Paneth cells. Graphical Abstract This Review discusses biological functions of Paneth cells and their importance for intestinal homeostasis and organismal health.

Key Points Females are more immunoreactive than males and, although sex hormones have an important role in immune functions, the X chromosome is fundamental in shaping sex-specific immune responses. X-linked specific diseases usually affect only males, simply because they are hemizygous for X chromosome alleles. The fact that females carry two X chromosomes, and therefore two different allelic options to be used by cells, means that they have two possible physiological responses. Mosaicism, caused by X chromosome inactivation, is one mechanism by which females can have an immune advantage over males, but there are also other features associated with the X chromosome that can modulate differences between female and male immune responses and even lead to immunological differences between individual females. Although X chromosome inactivation is expected to balance the levels of female and male gene expression, several genes located in the non-recombining regions of the sex chromosomes can escape inactivation, and females may have elevated gene expression of these genes. Moreover, females may present extreme skewing of X chromosome inactivation and show overrepresentation of one of the parental X chromosomes. Escape from X chromosome silencing and X inactivation skewing may account for immune differences between the sexes. These mechanisms may be involved in the development of autoimmunity, as skewed X chromosome inactivation or reactivation of parts of the inactive X chromosome can lead to the breakdown of self tolerance. The number of X-linked genes and microRNAs with an identified role in immunity is increasing, and it is possible that naturally occurring variations in these genes and microRNAs account for immunological differences between genders. This Review describes the mechanisms by which the X chromosome regulates immune responses. The authors discuss how the effects of this chromosome can account for many of the immunological differences, such as altered susceptibility to infection or autoimmune disease, that occur between the sexes. In response to various immune challenges, females show better survival than males; the X chromosome has an important role in this immunological advantage. X chromosome-linked diseases are usually restricted to males, who have only one copy of the X chromosome; however, females are more prone to autoimmune diseases, and the X chromosome may be involved in the breakdown of self tolerance. Several hypotheses have been proposed in recent years that support a role for the X chromosome in shaping autoimmune responses. Here, we review the main mechanisms responsible for increased immune activity in females. This provides a survival advantage in the face of pathogenic insult but can also enhance the susceptibility of females to autoimmunity.

The first Food and Drug Administration-(FDA)-approved drugs were small, chemically-manufactured and highly active molecules with possible off-target effects, followed by protein-based medicines such as antibodies. Conventional antibodies bind a specific protein and are becoming increasingly important in the therapeutic landscape. A very prominent class of biologicals are the anti-tumor necrosis factor (TNF) drugs that are applied in several inflammatory diseases that are characterized by dysregulated TNF levels. Marketing of TNF inhibitors revolutionized the treatment of diseases such as Crohn’s disease. However, these inhibitors also have undesired effects, some of them directly associated with the inherent nature of this drug class, whereas others are linked with their mechanism of action, being pan-TNF inhibition. The effects of TNF can diverge at the level of TNF format or receptor, and we discuss the consequences of this in sepsis, autoimmunity and neurodegeneration. Recently, researchers tried to design drugs with reduced side effects. These include molecules with more specificity targeting one specific TNF format or receptor, or that neutralize TNF in specific cells. Alternatively, TNF-directed biologicals without the typical antibody structure are manufactured. Here, we review the complications related to the use of conventional TNF inhibitors, together with the anti-TNF alternatives and the benefits of selective approaches in different diseases.

Protein–protein interactions (PPIs) underlie most biological processes. An increasing interest to investigate the unexplored potential of PPIs in drug discovery is driven by the need to find novel therapeutic targets for a whole range of diseases with a high unmet medical need. To date, PPI inhibition with small molecules is the mechanism that has most often been explored, resulting in significant progress towards drug development. However, also PPI stabilization is gradually gaining ground. In this review, we provide a focused overview of a number of PPIs that control critical regulatory pathways and constitute targets for the design of novel therapeutics. We discuss PPI-modulating small molecules that are already pursued in clinical trials. In addition, we review a number of PPIs that are still under preclinical investigation but for which preliminary data support their use as therapeutic targets.

Glucocorticoid-induced (GC) and hypoxia-induced transcriptional responses play an important role in tissue homeostasis and in the regulation of cellular responses to stress and inflammation. Evidence exists that there is an important crosstalk between both GC and hypoxia effects. Hypoxia is a pathophysiological condition to which cells respond quickly in order to prevent metabolic shutdown and death. The hypoxia inducible factors (HIFs) are the master regulators of oxygen homeostasis and are responsible for the ability of cells to cope with low oxygen levels. Maladaptive responses of HIFs contribute to a variety of pathological conditions including acute mountain sickness (AMS), inflammation and neonatal hypoxia-induced brain injury. Synthetic GCs which are analogous to the naturally occurring steroid hormones (cortisol in humans, corticosterone in rodents), have been used for decades as anti-inflammatory drugs for treating pathological conditions which are linked to hypoxia (i.e. asthma, ischemic injury). In this review, we investigate the crosstalk between the glucocorticoid receptor (GR), and HIFs. We discuss possible mechanisms by which GR and HIF influence one another, in vitro and in vivo , and the therapeutic effects of GCs on HIF-mediated diseases.

Here, we identified release of extracellular vesicles (EVs) by the choroid plexus epithelium (CPE) as a new mechanism of blood–brain communication. Systemic inflammation induced an increase in EVs and associated pro‐inflammatory miRNAs, including miR‐146a and miR‐155, in the CSF. Interestingly, this was associated with an increase in amount of multivesicular bodies (MVBs) and exosomes per MVB in the CPE cells. Additionally, we could mimic this using LPS‐stimulated primary CPE cells and choroid plexus explants. These choroid plexus‐derived EVs can enter the brain parenchyma and are taken up by astrocytes and microglia, inducing miRNA target repression and inflammatory gene up‐regulation. Interestingly, this could be blocked in vivo by intracerebroventricular (icv) injection of an inhibitor of exosome production. Our data show that CPE cells sense and transmit information about the peripheral inflammatory status to the central nervous system (CNS) via the release of EVs into the CSF, which transfer this pro‐inflammatory message to recipient brain cells. Additionally, we revealed that blockage of EV secretion decreases brain inflammation, which opens up new avenues to treat systemic inflammatory diseases such as sepsis. Synopsis New mechanism of blood–brain communication by the choroid plexus epithelial cells: uniquely positioned between blood and brain, choroid plexus epithelial cells release extracellular vesicles upon peripheral inflammation and transfer a pro‐inflammatory message to the brain. Systemic inflammation induces the release of miRNA‐containing extracellular vesicles by the choroid plexus epithelium cells into the cerebrospinal fluid. Choroid plexus epithelium‐derived EVs are able to cross the ependymal cells lining the ventricles and reach the brain parenchyma, and they are taken up by astrocytes and microglia. The choroid plexus epithelium‐derived EVs transfer a pro‐inflammatory signal to the brain. Graphical Abstract New mechanism of blood–brain communication by the choroid plexus epithelial cells: uniquely positioned between blood and brain, choroid plexus epithelial cells release extracellular vesicles upon peripheral inflammation and transfer a pro‐inflammatory message to the brain.

Mouse inbred strains remain essential in science. We have analyzed the publicly available genome sequences of 36 popular inbred strains and provide lists for each strain of protein-coding genes that acquired sequence variations that cause premature STOP codons, loss of STOP codons and single nucleotide polymorphisms, and short in-frame insertions and deletions. Our data give an overview of predicted defective proteins, including predicted impact scores, of all these strains compared with the reference mouse genome of C57BL/6J. These data can also be retrieved via a searchable website (mousepost.be) and allow a global, better interpretation of genetic background effects and a source of naturally defective alleles in these 36 sequenced classical and high-priority mouse inbred strains.