Repression of the aryl-hydrocarbon receptor prevents oxidative stress and ferroptosis of intestinal intraepithelial lymphocytes.

The aryl-hydrocarbon receptor (AHR) is a ligand-activated transcription factor that buoys intestinal immune responses. AHR induces its own negative regulator, the AHR repressor (AHRR). Here, we show that AHRR is vital to sustaining intestinal intraepithelial lymphocytes (IELs). AHRR deficiency reduced IEL representation in a cell-intrinsic fashion. Single-cell RNA sequencing revealed an oxidative stress profile in Ahrr-/- IELs. AHRR deficiency unleashed AHR-induced expression of CYP1A1, a monooxygenase that generates reactive oxygen species, increasing redox imbalance, lipid peroxidation, and ferroptosis in Ahrr-/- IELs. Dietary supplementation with selenium or vitamin E to restore redox homeostasis rescued Ahrr-/- IELs. Loss of IELs in Ahrr-/- mice caused susceptibility to Clostridium difficile infection and dextran sodium-sulfate-induced colitis. Inflamed tissue of inflammatory bowel disease patients showed reduced Ahrr expression that may contribute to disease. We conclude that AHR signaling must be tightly regulated to prevent oxidative stress and ferroptosis of IELs and to preserve intestinal immune responses.

Glutamine alleviates intestinal injury in a murine burn sepsis model by maintaining intestinal intraepithelial lymphocyte homeostasis.

Intestinal intraepithelial lymphocytes (IELs) play a sentinel role in the mucosal immune system because of their unique anatomical location in the epithelial layer. The disruption of IEL homeostasis is implicated in driving the intestinal injury of many typical inflammatory disorders, such as inflammatory bowel disease (IBD) and sepsis. Therefore, it is meaningful to alleviate intestinal injury by restoring IEL homeostasis in disease conditions. This study explores the effects of glutamine on intestinal IEL homeostasis in a murine model of burn sepsis. We report that glutamine inhibits inflammatory response and reduces injury in the small intestine of burn septic mice. This effect is attributed to the maintaining of IEL homeostasis by suppressing apoptosis and restoring the disrupted subpopulation balance induced by burn sepsis. Mechanistically, we show that glutamine does not affect the IL-15 dependent mechanisms that drive the maintenance and differentiation of IELs. Instead, glutamine sustains IEL homeostasis by upregulate aryl hydrocarbon receptor (AHR) and interleukin (IL)-22 transcription and expression. Consistently, the protective roles of glutamine in burn septic mice were repressed by further supplement with an AHR antagonist CH-223191. Collectively, our study reveals a new role of glutamine to maintain IEL homeostasis by activating the AHR signaling pathway, which in turn ameliorates intestinal injury in burn sepsis.

Prolapsus muqueux de l'urêtre de la petite fille: diagnostic et traitement / Girl mucosal urethral prolapse: diagnosis and treatment

Defi ned as circumferential eversion of the epithelium of the distal urethra, mucosal prolapse of the urethra occurs in the girl child. The diagnosis is clinical but may be overlooked or confused with other conditions. Treatment remains controversial. The aim was to describe the anatomical and therapeutic aspects. Methods. This was a retrospective and descriptive study over 5 years. Age, time of admission and circumstances of occurrence were analysed. Clinical aspects were based on the length of the prolapse (small less than 1 cm, medium: between 1 and 2 cm, large more than 2 cm), the colour of the prolapse and the presence or absence of bleeding. The treatment was medical (hormonal) and surgical in case of failure of hormonal treatment. The evaluation of the results was based on the occurrence of recurrence and urinary incontinence. The average follow-up was 18 months. Results. Twenty-one patients were included in the study with a mean age of 6.5 years. The mean time to onset was 12.4 days. Vulvar bleeding was the reason for consultation in n=9 patients. The prolapse was large in 12 patients, medium in 9 patients and small in 3 patients. The prolapse was violaceous in 15 patients. Medical

Activation of chicken gamma-delta T lymphocytes by a purified ulvan extract.

Chicken γδ T lymphocytes are present in a variety of tissues such as blood, spleen and intestine. They constitute a major cytotoxic population. In chicken, Salmonella immunization as well as vaccination against Newcastle disease virus are accompanied by an increase of γδ T lymphocytes in peripheral blood, which may be activated, and thus represent a protective immune response. It has been published that activation of avian γδ T cells can occur in a MHC non-restricted manner. Ulvans are complex sulfated polysaccharides composed of disaccharide repetitions found in the cell walls of green algae belonging to the genus Ulva. We recently demonstrated that a purified ulvan extract activates chicken heterophils and monocytes in vivo through TLR2 and TLR4 receptors when given in drinking water. We demonstrate here, that the same extract given once in drinking water at 25 and 50 mg/l, results in increased membrane expression of Major Histocompatibility Complex class 2 as soon as day 2, as detected using flow cytometry. We conclude chicken γδ T lymphocytes to be activated, or at least primed, in vivo, with the extract. Further experiments are required to fully understand whether their activation or priming is the result of direct and/or indirect mechanisms.

Fingolimod ameliorates imiquimod-induced psoriasiform dermatitis by sequestrating interleukin-17-producing ?d T cells in secondary lymph nodes.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease. Interleukin (IL)-17A plays a key role in the pathogenesis of psoriasis. Fingolimod, which is available for the treatment of multiple sclerosis, exerts anti-inflammatory effects by sequestrating inflammatory lymphocytes in secondary lymphoid tissues and the thymus. The effect of fingolimod on psoriasis has not been reported yet. OBJECTIVE: Our objectives were to investigate the effect of fingolimod on psoriasis utilizing mice with imiquimod (IMQ)-induced psoriasiform dermatitis, and explore the possibility of fingolimod as a therapeutic agent for psoriasis. METHODS: Psoriasiform dermatitis was induced by imiquimod application on murine shaved back skin for six days. Fingolimod prepared in phosphate-buffered saline (PBS), or PBS alone as a control, was administered intraperitoneally daily from days 0 to 5. RESULTS: Fingolimod ameliorated IMQ-induced psoriasis dermatitis clinically and histologically. On day 6, the mRNA expression level of IL-17A was lower in the skin of fingolimod-treated mice than in that of PBS-treated mice, whereas it was higher in the inguinal lymph nodes of fingolimod-treated mice than in those of PBS-treated mice. Flow cytometric analyses revealed that fingolimod reduced IL-17A-producing ?d T cells infiltrating into the skin, whereas it increased these cells in the inguinal lymph nodes. Fingolimod inhibited egress of Langerhans cells from the skin to lymph nodes. CONCLUSION: Our results demonstrated that fingolimod showed effectiveness for IMQ-induced psoriasiform dermatitis by hindering the emigration of IL-17A-producing ?d T cells from the lymph nodes to the skin, and suggest that fingolimod is a promising candidate for the treatment of psoriasis.

Protective Effect of Tong-Qiao-Huo-Xue Decoction on Inflammatory Injury Caused by Intestinal Microbial Disorders in Stroke Rats.

Tong-Qiao-Huo-Xue Decoction (TQHXD) is a classic traditional Chinese medicine prescription for treating cerebral ischemia. The purpose of this study was to investigate the effect of TQHXD on intervening inflammatory response of ischemic stroke by regulating intestinal flora and repairing the intestinal barrier. A rat model of cerebral ischemia was established using middle cerebral artery occlusion (MCAO) and behavioral scores were performed. Additionally, the high throughput 16S ribosomal DNA (rDNA) sequence of intestinal bacteria in fecal samples of rat was also carried out. Our results showed that TQHXD could change the main components of intestinal flora in stroke rats, and reduced the excessive increase of Bacteroidetes, and also regulated the abnormal changes of abundance of some flora as well. In addition, the intestinal epithelial barrier was damaged after stroke, allowing bacterial metabolites to enter the blood, while TQHXD had an improved effect on this phenomenon. Meanwhile, pathological changes in the brain tissue and infarct volume were also alleviated by TQHXD. Due to the disorder of the intestinal flora and the destruction of the barrier, the peripheral immune imbalance caused an inflammatory reaction. TQHXD improved the imbalance of T cells, and inhibited the inflammatory response. Finally, the therapeutic transplantation of fecal microbiota also improved the outcome of stroke in rats. Our presented results suggest that TQHXD may improve the gut microbiota disorder and its induced inflammatory response after stroke, which could be a new target and mechanism for the treatment of stroke.

Effect of pre- and post-weaning dietary supplementation with arginine and glutamine on rabbit performance and intestinal health.

BACKGROUND: The purpose of the present study was to assess if the exposure to glutamine (Gln), arginine (Arg) or their combination from pregnancy, through the maternal diet, to a post weaning supplemented diet, can stimulate litter performance, gut development and immune function. To this end does and their litters were fed the same basal diet no supplemented (control C), or supplemented with 0.4% Gln, 0.4% Arg, or 0.4 Gln + 0.4 Arg. Rabbits were weaned at 25 d of age and fed the same experimental diet as their mothers for 10 additional days (35 d of age). Bacterial translocation to mesenteric lymph nodes (MLN) at 6 d of age and intestinal histology, enzymatic activity, phenotypical and functional analysis of intraepithelial lymphocytes (IEL) from the appendix were determined at 6, 25 and 35 d of age. RESULTS: No significant differences on animal performance or mortality rates were observed among dietary treatments. However, kits from rabbit does supplemented with Gln tended (P ≤ 0.10) to reduce the translocation of total number of both aerobic and facultative anaerobic bacteria to the MLN. Also, rabbits fed the Gln supplemented diets maintained intestinal villous height at weaning compared to the non-supplemented diets (P < 0.05). The proportions of CD45+CD4+ and CD45+CD8+ IEL in the appendix were not affected by dietary means. However, in rabbits IEL at weaning dietary Gln significantly upregulated IL-2 and downregulated IL-6 expression. CONCLUSIONS: Despite a lack of effect on performance and mortality the inclusion of 0.4% Gln has a positive effect by maintaining intestinal villous height and modulating the cytokine profile at weaning. The supplementation with Arg or Arg + Gln at the selected doses in this study did not exert positive effects on rabbit intestinal health.

Influence of Moringa oleifera extract, vitamin C, and sodium bicarbonate on heat stress-induced HSP70 expression and cellular immune response in rabbits.

The current study aimed to test the effect of Moringa oleifera extract (MOE), vitamin (Vit) C, and sodium bicarbonate (NaHCO3) on heat stress (HS)-induced alterations in rabbits. Five groups of rabbits were designed as control, HS, HS + MOE, HS + Vit C, and HS + NaHCO3. HS groups were exposed to high temperatures, while treatments were given in drinking water for 6 weeks. Levels of blood cortisol, leptin, IFN-γ, TNF-α, and IL-10 were assayed using ELISA, while adrenaline was assayed calorimetrically. Expression of HSP70, FOXP3, T cell receptor (TCR) γ, and δ mRNA was tested using real-time (RT)-PCR, while HSP70 protein expression was tested using western blotting in liver and kidney tissues. Infiltration of regulatory T cells (Treg; CD25+) and NK (CD56+) cells were tested using immunohistochemistry (IHC). The levels of liver enzymes (ALT & AST), urea, and creatinine were assayed calorimetrically, while body weight gain (BWG) and feed conversion ratio (FCR) were calculated. The results showed increased levels of cortisol, adrenaline, leptin, IFN-γ, TNF-α, ALT, AST, urea, and creatinine but decreased IL-10 in the HS group. Increased expression of HSP70 on both mRNA and protein levels was associated with increased NK and γδ T cells versus decreased Treg cell infiltration in liver and kidney tissues of the HS group. In the same group, BWG was decreased, while FCR was increased with respect to the control group. All treatments used in this study reversed the effects of HS significantly. In conclusion, MOE, Vit C, and NaHCO3 can be added to rabbit diets for the amelioration of HS-induced symptoms.

Differential ratios of fish/corn oil ameliorated the colon carcinoma in rat by altering intestinal intraepithelial CD8+ T lymphocytes, dendritic cells population and modulating the intracellular cytokines.

Intraepithelial lymphocytes (IELs) impart a crucial role in maintaining intestinal homeostasis, yet their role in colon cancer pathogenesis remains unknown. Here, we posited that the modulation of intestinal immune response via dietary interventions might be an implacable strategy in restraining colon carcinoma. In the above context, we studied the effect of differential ratios of fish oil (FO) and corn oil (CO) on the gut immune response in experimentally induced colon cancer. Male Wistar rats were divided into six groups: Group I obtained purified diet while Groups II and III were fed on the diet supplemented with differential ratios of FO and CO i.e. 1:1 and 2.5:1, respectively. The groups were further subdivided into control and carcinogenic group, treated with ethylenediaminetetraacetic acid (EDTA) or N,N'-dimethylhydrazine dihydrochloride (DMH), respectively. Initiation phase comprised the animals sacrificed 48 h after the last injection whereas, the post -initiation phase was constituted by animals sacrificed 12 weeks after the treatment regimen. CD8+ T cells, CD8/αß TCR cells, dendritic cells increased significantly on treatment with DMH as compared to control. However, on treatment with differential ratios of FO and CO these cells decreased significantly. The intracellular cytokine i.e. interferon gamma (IFN-γ) and cytotoxic granules component i.e Perforin and Granzyme decreased significantly in the initiation phase but in the post-initiation phase IFN-γ and Perforin increased considerably on carcinogen treatment as compared to the control group. On treatment with FO and CO in the initiation phase the IFN-γ, Perforin and Granzyme expression increased significantly. However, in the post-initiation phase treatment with differential ratios of FO and CO led to a significant decrease in the IFN-γ, Perforin and increase in Granzyme was observed in these groups. Altogether, FO supplementation appeared to activate the immune response that may further attenuate the process of carcinogenesis, in a dose and time-dependent manner.

Pharmacological inhibition of RORγt suppresses the Th17 pathway and alleviates arthritis in vivo.

Retinoic acid receptor-related-orphan-receptor-C (RORγt) is the key transcription factor that is driving the differentiation of IL-17 producing T-helper 17 (Th17) cells that are implicated in the pathology of various autoimmune and inflammatory diseases. Based on the importance of RORγt in promoting Th17-driven pathology, there is considerable interest to develop low-molecular-weight compounds with the aim of inhibiting the transcriptional activity of this nuclear hormone receptor. In this article, we describe the in vitro and in vivo pharmacology of a potent and selective small-molecular-weight RORγt inverse agonist. The compound binds to the ligand binding domain (LBD) of RORγt leading to displacement of a co-activator peptide. We show for the first time that a RORγt inverse agonist down-regulates permissive histone H3 acetylation and methylation at the IL17A and IL23R promoter regions, thereby providing insight into the transcriptional inhibition of RORγt-dependent genes. Consistent with this, the compound effectively reduced IL-17A production by polarized human T-cells and γδT-cells and attenuated transcription of RORγt target genes. The inhibitor showed good in vivo efficacy in an antigen-induced arthritis model in rats and reduced the frequencies of IL-17A producing cells in ex vivo recall assays. In summary, we demonstrate that inhibiting RORγt by a low-molecular-weight inhibitor results in efficient and selective blockade of the pro-inflammatory Th17/IL-17A pathway making it an attractive target for Th17-mediated disorders.