Polyphenol and glucosinolate-derived AhR modulators regulate GPR15 expression on human CD4+ T cells.

Diets high in fruit and vegetables are perceived to be beneficial for intestinal homeostasis, in health as well as in the context of inflammatory bowel diseases (IBDs). Recent breakthroughs in the field of immunology have highlighted the importance of the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) as a critical regulator of mucosal immunity, including the intestinal trafficking of CD4+ helper T cells, an immune cell subset implicated in a wide range of homeostatic and pathogenic processes. Specifically, the AhR has been shown to directly regulate the expression of the chemoattractant receptor G Protein-Coupled Receptor 15 (GPR15) on CD4+ T cells. GPR15 is an important gut homing marker whose expression on CD4+ T cells in the peripheral circulation is elevated in patients suffering from ulcerative colitis, raising the possibility that, in this setting, the beneficial effect of a diet rich in fruits and vegetables may be mediated through the modulation of GPR15 expression. To address this, we screened physiologically-relevant polyphenol and glucosinolate metabolites for their ability to affect both AhR activity and GPR15 expression. Our complementary approach and associated findings suggest that polyphenol and glucosinolate metabolites can regulate GPR15 expression on human CD4+ T cells in an AhR-dependent manner.

MR1-dependence of unmetabolized folic acid side-effects.

The fortification of flour with folic acid for the prevention of neural tube defects (NTD) is currently mandated in over eighty countries worldwide, hence compelling its consumption by the greater part of the world's population. Notwithstanding its beneficial impact on rates of NTD, pervasive folic acid supplementation has invariably led to additive daily intakes reaching well beyond their original target, resulting in the circulation of unmetabolized folic acid. Associated idiopathic side-effects ranging from allergies to cancer have been suggested, albeit inconclusively. Herein, we hypothesize that their inconsistent detection and elusive etiology are linked to the in vivo generation of the immunosuppressive folic acid metabolite 6-formylpterin, which interferes with the still emerging and varied functions of Major Histocompatibility Complex-related molecule 1 (MR1)-restricted T cells. Accordingly, we predict that fortification-related adverse health outcomes can be eliminated by substituting folic acid with the bioequivalent folate vitamer 5-methyltetrahydrofolate, which does not break down into 6-formylpterin.

Conventional laboratory housing increases morbidity and mortality in research rodents: results of a meta-analysis.

BACKGROUND: Over 120 million mice and rats are used annually in research, conventionally housed in shoebox-sized cages that restrict natural behaviours (e.g. nesting and burrowing). This can reduce physical fitness, impair thermoregulation and reduce welfare (e.g. inducing abnormal stereotypic behaviours). In humans, chronic stress has biological costs, increasing disease risks and potentially shortening life. Using a pre-registered protocol ( https://atrium.lib.uoguelph.ca/xmlui/handle/10214/17955 ), this meta-analysis therefore tested the hypothesis that, compared to rodents in 'enriched' housing that better meets their needs, conventional housing increases stress-related morbidity and all-cause mortality. RESULTS: Comprehensive searches (via Ovid, CABI, Web of Science, Proquest and SCOPUS on May 24 2020) yielded 10,094 publications. Screening for inclusion criteria (published in English, using mice or rats and providing 'enrichments' in long-term housing) yielded 214 studies (within 165 articles, using 6495 animals: 59.1% mice; 68.2% male; 31.8% isolation-housed), and data on all-cause mortality plus five experimentally induced stress-sensitive diseases: anxiety, cancer, cardiovascular disease, depression and stroke. The Systematic Review Center for Laboratory animal Experimentation (SYRCLE) tool assessed individual studies' risks of bias. Random-effects meta-analyses supported the hypothesis: conventional housing significantly exacerbated disease severity with medium to large effect sizes: cancer (SMD = 0.71, 95% CI = 0.54-0.88); cardiovascular disease (SMD = 0.72, 95% CI = 0.35-1.09); stroke (SMD = 0.87, 95% CI = 0.59-1.15); signs of anxiety (SMD = 0.91, 95% CI = 0.56-1.25); signs of depression (SMD = 1.24, 95% CI = 0.98-1.49). It also increased mortality rates (hazard ratio = 1.48, 95% CI = 1.25-1.74; relative median survival = 0.91, 95% CI = 0.89-0.94). Meta-regressions indicated that such housing effects were ubiquitous across species and sexes, but could not identify the most impactful improvements to conventional housing. Data variability (assessed via coefficient of variation) was also not increased by 'enriched' housing. CONCLUSIONS: Conventional housing appears sufficiently distressing to compromise rodent health, raising ethical concerns. Results also add to previous work to show that research rodents are typically CRAMPED (cold, rotund, abnormal, male-biased, poorly surviving, enclosed and distressed), raising questions about the validity and generalisability of the data they generate. This research was funded by NSERC, Canada.

Practical Approach To Explore the Effects of Polyphenols on Aryl Hydrocarbon Receptor Regulated Immune Function.

The ligand-activated aryl hydrocarbon receptor (AhR) is an important molecular regulator of immune function, whose activity can be modulated by dietary glucosinolate- and tryptophan-derived metabolites. In contrast, the potential use of polyphenols as dietary regulators of AhR-dependent immunity remains unclear. In this perspective, we discuss how cellular metabolism may alter the net effect of polyphenols on AhR, thus potentially reconciling some of the conflicting observations reported in the literature. We further provide a methodological roadmap, across the fields of immunology, metabolomics, and gut microbial ecology, to explore the potential effects of polyphenol-rich diets on AhR-regulated immune function in humans.

IL-22 Preserves Gut Epithelial Integrity and Promotes Disease Remission during Chronic Salmonella Infection.

The cytokine IL-22 is rapidly induced at barrier surfaces where it regulates host-protective antimicrobial immunity and tissue repair but can also enhance disease severity in some chronic inflammatory settings. Using the chronic Salmonella gastroenteritis model, Ab-mediated neutralization of IL-22 impaired intestinal epithelial barrier integrity and, consequently, exaggerated expression of proinflammatory cytokines. As disease normally resolved, neutralization of IL-22 caused luminal narrowing of the cecum-a feature reminiscent of fibrotic strictures seen in Crohn disease patients. Corresponding to the exaggerated immunopathology caused by IL-22 suppression, Salmonella burdens in the gut were reduced. This enhanced inflammation and pathogen clearance was associated with alterations in gut microbiome composition, including the overgrowth of Bacteroides acidifaciens Our findings thus indicate that IL-22 plays a protective role by limiting infection-induced gut immunopathology but can also lead to persistent pathogen colonization.

Inhibition of Methyltransferase Setd7 Allows the In Vitro Expansion of Myogenic Stem Cells with Improved Therapeutic Potential.

The development of cell therapy for repairing damaged or diseased skeletal muscle has been hindered by the inability to significantly expand immature, transplantable myogenic stem cells (MuSCs) in culture. To overcome this limitation, a deeper understanding of the mechanisms regulating the transition between activated, proliferating MuSCs and differentiation-primed, poorly engrafting progenitors is needed. Here, we show that methyltransferase Setd7 facilitates such transition by regulating the nuclear accumulation of ß-catenin in proliferating MuSCs. Genetic or pharmacological inhibition of Setd7 promotes in vitro expansion of MuSCs and increases the yield of primary myogenic cell cultures. Upon transplantation, both mouse and human MuSCs expanded with a Setd7 small-molecule inhibitor are better able to repopulate the satellite cell niche, and treated mouse MuSCs show enhanced therapeutic potential in preclinical models of muscular dystrophy. Thus, Setd7 inhibition may help bypass a key obstacle in the translation of cell therapy for muscle disease.

G9a regulates group 2 innate lymphoid cell development by repressing the group 3 innate lymphoid cell program.

Innate lymphoid cells (ILCs) are emerging as important regulators of homeostatic and disease-associated immune processes. Despite recent advances in defining the molecular pathways that control development and function of ILCs, the epigenetic mechanisms that regulate ILC biology are unknown. Here, we identify a role for the lysine methyltransferase G9a in regulating ILC2 development and function. Mice with a hematopoietic cell-specific deletion of G9a (Vav.G9a(-/-) mice) have a severe reduction in ILC2s in peripheral sites, associated with impaired development of immature ILC2s in the bone marrow. Accordingly, Vav.G9a(-/-) mice are resistant to the development of allergic lung inflammation. G9a-dependent dimethylation of histone 3 lysine 9 (H3K9me2) is a repressive histone mark that is associated with gene silencing. Genome-wide expression analysis demonstrated that the absence of G9a led to increased expression of ILC3-associated genes in developing ILC2 populations. Further, we found high levels of G9a-dependent H3K9me2 at ILC3-specific genetic loci, demonstrating that G9a-mediated repression of ILC3-associated genes is critical for the optimal development of ILC2s. Together, these results provide the first identification of an epigenetic regulatory mechanism in ILC development and function.

Mast cells in human health and disease.

Mast cells are primarily known for their role in defense against pathogens, particularly bacteria; neutralization of venom toxins; and for triggering allergic responses and anaphylaxis. In addition to these direct effector functions, activated mast cells rapidly recruit other innate and adaptive immune cells and can participate in "tuning" the immune response. In this review we touch briefly on these important functions and then focus on some of the less-appreciated roles of mast cells in human disease including cancer, autoimmune inflammation, organ transplant, and fibrosis. Although it is difficult to formally assign causal roles to mast cells in human disease, we offer a general review of data that correlate the presence and activation of mast cells with exacerbated inflammation and disease progression. Conversely, in some restricted contexts, mast cells may offer protective roles. For example, the presence of mast cells in some malignant or cardiovascular diseases is associated with favorable prognosis. In these cases, specific localization of mast cells within the tissue and whether they express chymase or tryptase (or both) are diagnostically important considerations. Finally, we review experimental animal models that imply a causal role for mast cells in disease and discuss important caveats and controversies of these findings.