Extra-adrenal glucocorticoid synthesis in the intestinal epithelium: more than a drop in the ocean?

Glucocorticoids (GC) are lipophilic hormones commonly used as therapeutics in acute and chronic inflammatory disorders such as inflammatory bowel disease due to their attributed anti-inflammatory and immunosuppressive actions. Although the adrenal glands are the major source of endogenous GC, there is increasing evidence for the production of extra-adrenal GC in the brain, thymus, skin, vasculature, and the intestine. However, the physiological relevance of extra-adrenal-produced GC remains still ambiguous. Therefore, this review attracts attention to discuss possible biological benefits of extra-adrenal-synthesized GC, especially focusing on the impact of locally synthesized GC in the regulation of intestinal immune response

The Shelhigh No-React® bovine internal mammary artery: a questionable alternative conduit in coronary bypass surgery?

Background: Increasing age and comorbidities among patients undergoing coronary artery bypass surgery (CABG) stimulates the exhaustive research for alternative grafts. No-React® treatment should render the tissue resistant against degeneration and reduce early inflammatory response. The aim of the present study was an invasive assessment of the patency of No-React® bovine internal mammary artery (NRIMA grafts) used as bypass conduit in CABG surgery. Patients and methods: Nineteen NRIMA grafts were used in 17 patients (2.9%) out of a total of 572 patients undergoing CABG surgery within a 12-month period. All intraoperative data were assessed and in-hospital outcome was analysed. Follow-up examination was performed 7.0±4.0 months after initial surgery, including clinical status and coronary angiography to assess patency of the NRIMA grafts. Results: Average perioperative flow of all NRIMA grafts was 71±60ml/min. One patient died in hospital due to a multi-organ failure. Four patients refused invasive assessment. Follow-up was complete in 12 patients with overall 13 NRIMA grafts. Nine NRIMA grafts (69.2%) were used for the right coronary system, two NRIMA grafts (15.4%) on the LAD and two on the circumflex artery. Graft patency was 23.1% and was independent of the intraoperative flow measurement. Conclusions: NRIMA grafts show a very low patency and cannot be recommended as coronary bypass graft conduits. Patency was independent of the perioperative flow, assessed by Doppler ultrasound. Because of this unsatisfying observation, this type of graft should be utilised as a last resource conduit and used only to revascularise less important target vessels, such as the end branches of the right coronary arter

The nuclear receptor LRH-1 critically regulates extra-adrenal glucocorticoid synthesis in the intestine

The nuclear receptor liver receptor homologue-1 (LRH-1, NR5A2) is a crucial transcriptional regulator of many metabolic pathways. In addition, LRH-1 is expressed in intestinal crypt cells where it regulates the epithelial cell renewal and contributes to tumorigenesis through the induction of cell cycle proteins. We have recently identified the intestinal epithelium as an important extra-adrenal source of immunoregulatory glucocorticoids. We show here that LRH-1 promotes the expression of the steroidogenic enzymes and the synthesis of corticosterone in murine intestinal epithelial cells in vitro. Interestingly, LRH-1 is also essential for intestinal glucocorticoid synthesis in vivo, as LRH-1 haplo-insufficiency strongly reduces the intestinal expression of steroidogenic enzymes and glucocorticoid synthesis upon immunological stress. These results demonstrate for the first time a novel role for LRH-1 in the regulation of intestinal glucocorticoid synthesis and propose LRH-1 as an important regulator of intestinal tissue integrity and immune homeostasis

IL-20 subfamily cytokines impair the oesophageal epithelial barrier by diminishing filaggrin in eosinophilic oesophagitis.

OBJECTIVE Disruption of the epithelial barrier plays an essential role in developing eosinophilic oesophagitis (EoE), a disease defined by type 2 helper T cell (Th2)-mediated food-associated and aeroallergen-associated chronic inflammation. Although an increased expression of interleukin (IL)-20 subfamily members, IL-19, IL-20 and IL-24, in Th2-mediated diseases has been reported, their function in EoE remains unknown. DESIGN Combining transcriptomic, proteomic and functional analyses, we studied the importance of the IL-20 subfamily for EoE using patient-derived oesophageal three-dimensional models and an EoE mouse model. RESULTS Patients with active EoE have increased expression of IL-20 subfamily cytokines in the oesophagus and serum. In patient-derived oesophageal organoids stimulated with IL-20 cytokines, RNA sequencing and mass spectrometry revealed a downregulation of genes and proteins forming the cornified envelope, including filaggrins. On the contrary, abrogation of IL-20 subfamily signalling in Il20R2 -/- animals resulted in attenuated experimental EoE reflected by reduced eosinophil infiltration, lower Th2 cytokine expression and preserved expression of filaggrins in the oesophagus. Mechanistically, these observations were mediated by the mitogen-activated protein kinase (MAPK); extracellular-signal regulated kinases (ERK)1/2) pathway. Its blockade prevented epithelial barrier impairment in patient-derived air-liquid interface cultures stimulated with IL-20 cytokines and attenuated experimental EoE in mice. CONCLUSION Our findings reveal a previously unknown regulatory role of the IL-20 subfamily for oesophageal barrier function in the context of EoE. We propose that aberrant IL-20 subfamily signalling disturbs the oesophageal epithelial barrier integrity and promotes EoE development. Our study suggests that specific targeting of the IL-20 subfamily signalling pathway may present a novel strategy for the treatment of EoE

TNF suppresses acute intestinal inflammation by inducing local glucocorticoid synthesis

Although tumor necrosis factor (α) (TNF) exerts proinflammatory activities in a variety of diseases, including inflammatory bowel disease, there is increasing evidence for antiinflammatory actions of TNF. In contrast, glucocorticoids (GCs) are steroid hormones that suppress inflammation, at least in part by regulating the expression and action of TNF. We report that TNF induces extraadrenal production of immunoregulatory GCs in the intestinal mucosa during acute intestinal inflammation. The absence of TNF results in a lack of colonic GC synthesis and exacerbation of dextran sodium sulfate–induced colitis. TNF seems to promote local steroidogenesis by directly inducing steroidogenic enzymes in intestinal epithelial cells. Therapeutic administration of TNF induces GC synthesis in oxazolone-induced colitis and ameliorates intestinal inflammation, whereas inhibition of intestinal GC synthesis abrogates the therapeutic effect of TNF. These data show that TNF suppresses the pathogenesis of acute intestinal inflammation by promoting local steroidogenesis

Editorial: Microbiome-host-immune crosstalk : mining the microbiome: a treasure trove waiting to be unlocked

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Keep calm: the intestinal barrier at the interface of peace and war

Epithelial barriers have to constantly cope with both harmless and harmful stimuli. The epithelial barrier therefore serves as a dynamic and not static wall to safeguard its proper physiological function while ensuring protection. This is achieved through multiple defence mechanisms involving various cell types - epithelial and non-epithelial - that work in an integrated manner to build protective barriers at mucosal sites. Damage may nevertheless occur, due to pathogens, physical insults or dysregulated immune responses, which trigger a physiologic acute or a pathologic chronic inflammatory cascade. Inflammation is often viewed as a pathological condition, particularly due to the increasing prevalence of chronic inflammatory (intestinal) diseases. However, inflammation is also necessary for wound healing. The aetiology of chronic inflammatory diseases is incompletely understood and identification of the underlying mechanisms would reveal additional therapeutic approaches. Resolution is an active host response to end ongoing inflammation but its relevance is under-appreciated. Currently, most therapies aim at dampening inflammation at damaged mucosal sites, yet these approaches do not efficiently shut down the inflammation process nor repair the epithelial barrier. Therefore, future treatment strategies should also promote the resolution phase. Yet, the task of repairing the barrier can be an arduous endeavour considering its multiple integrated layers of defence - which is advantageous for damage prevention but becomes challenging to repair at multiple levels. In this review, using the intestines as a model epithelial organ and barrier paradigm, we describe the consequences of chronic inflammation and highlight the importance of the mucosae to engage resolving processes to restore epithelial barrier integrity and function. We further discuss the contribution of pre-mRNA alternative splicing to barrier integrity and intestinal homeostasis. Following discussions on current open questions and challenges, we propose a model in which resolution of inflammation represents a key mechanism for the restoration of epithelial integrity and function