Aryl Hydrocarbon Receptor Activation Promotes Effector CD4+ T Cell Homeostasis and Restrains Salt-sensitive Hypertension.

Excess dietary salt and salt-sensitivity contribute to cardiovascular disease. Distinct T cell phenotypic responses to high salt and hypertension as well as influences from environmental cues are not well understood. The aryl hydrocarbon receptor (AhR) is activated by dietary ligands, promoting T cell and systemic homeostasis.

Intestinal Barrier Function Declines During Polycystic Kidney Disease Progression.

Most patients with autosomal dominant polycystic kidney disease (ADPKD) develop kidney cysts due to germline mutations. In the kidney, loss impairs epithelial cell integrity and increases macrophage infiltration, contributing to cyst growth. Despite its role as the body's largest inflammatory cell reservoir, it has yet to be elucidated whether a similar phenotype presents in the intestines.

Racial and ethnic differences in diagnosis age and blood biomarkers in a pediatric inflammatory bowel disease cohort.

Objective: Prompt diagnosis of pediatric-onset inflammatory bowel disease (IBD) is crucial for preventing a complicated disease course; however, it is not well understood how social determinants of health might affect pediatric IBD diagnosis. This study examined differences in diagnosis age, biomarkers of disease severity, and anthropometrics with sociodemographic factors in a pediatric IBD cohort.

Methods: Pediatric IBD patients (n = 114) and their parents/caregivers were enrolled from the Children's of Alabama Pediatric IBD Clinic in Birmingham, Alabama.

Early Life Stress in Mice Leads to Impaired Colonic Corticosterone Production and Prolonged Inflammation Following Induction of Colitis.

Background: Early life stress (ELS) is an environmental trigger believed to promote increased risk of IBD. Our goal was to identify mechanisms whereby ELS in mice affects susceptibility to and/or severity of gut inflammation.

Methods: We utilized 2 published animal models of ELS.

Hedgehog blockade remodels the gut microbiota and the intestinal effector CD8 T cells in a mouse model of mammary carcinoma.

Given the gut microbiome's rise as a potential frontier in cancer pathogenesis and therapy, leveraging microbial analyses in the study of breast tumor progression and treatment could unveil novel interactions between commensal bacteria and disease outcomes. In breast cancer, the Hedgehog (Hh) signaling pathway is a potential target for treatment due to its aberrant activation leading to poorer prognoses and drug resistance. There are limited studies that have investigated the influences of orally administered cancer therapeutics, such as Vismodegib (a pharmacological, clinically used Hh inhibitor) on the gut microbiota.

Hydroxyproline stimulates inflammation and reprograms macrophage signaling in a rat kidney stone model.

Meals rich in oxalate are associated with calcium oxalate (CaOx) kidney stone disease. Hydroxy-L-proline (HLP) is an oxalate precursor found in milk and collagen-containing foods. HLP has been shown to induce CaOx crystal formation in rodents.

Mucus, commensals, and the immune system.

The immune system in the large intestine is separated from commensal microbes and comparatively rare enteric pathogens by a monolayer of diverse epithelial cells overlaid with a compact and adherent inner mucus layer and a looser outer mucus layer. Microorganisms, collectively referred to as the mucus-associated (MA) microbiota, physically inhabit this mucus barrier, resulting in a dynamic and incessant dialog to maintain both spatial segregation and immune tolerance. Recent major findings reveal novel features of the crosstalk between the immune system and mucus-associated bacteria in health and disease, as well as disease-related peripheral immune signatures indicative of host responses to these organisms.

Pirfenidone increases IL-10 and improves acute pancreatitis in multiple clinically relevant murine models.

Despite decades of research, there is no specific therapy for acute pancreatitis (AP). In the current study, we have evaluated the efficacy of pirfenidone, an antiinflammatory and antifibrotic agent that is approved by the FDA for treatment of idiopathic pulmonary fibrosis (IPF), in ameliorating local and systemic injury in AP. Our results suggest that treatment with pirfenidone in therapeutic settings (e.

ICOS ligand and IL-10 synergize to promote host-microbiota mutualism.

Genome-wide association studies have identified , which encodes the inducible costimulator igand (ICOSLG or ICOSL) as a susceptibility locus for inflammatory bowel disease. ICOSL has been implicated in the enhancement of pattern recognition receptor signaling in dendritic cells, induction of IL-10 production by CD4 T cells, and the generation of high-affinity antibodies to specific antigens-all of which can potentially explain its involvement in gastrointestinal inflammation. Here, we show that murine ICOSL deficiency results in significant enrichment of IL-10-producing CD4 T cells particularly in the proximal large intestine.

Early life stress in mice alters gut microbiota independent of maternal microbiota inheritance.

Exposure to early life stress (ELS) is associated with a greater risk of chronic disease development including depression and cardiovascular disease. Altered gut microbiota has been linked to both depression and cardiovascular disease in mice and humans. Rodent models of early life neglect are used to characterize the mechanistic links between early life stress (ELS) and the risk of disease later in life.

CD4 T cell activation and concomitant mTOR metabolic inhibition can ablate microbiota-specific memory cells and prevent colitis.

Microbiota-reactive CD4 T memory (T) cells are generated during intestinal infections and inflammation, and can revert to pathogenic CD4 T effector (T) cells, resulting in chronicity of inflammatory bowel disease (IBD). Unlike T cells, T cells have a low rate of metabolism unless they are activated by reencountering cognate antigen. Here, we show that the combination of cell activation and metabolic checkpoint inhibition (CAMCI), by targeting key metabolic regulators mTORC and AMPK, resulted in cell death and anergy, but enhanced the induction of the regulatory subset.

Bone marrow Tregs mediate stromal cell function and support hematopoiesis via IL-10.

The nonimmune roles of Tregs have been described in various tissues, including the BM. In this study, we comprehensively phenotyped marrow Tregs, elucidating their key features and tissue-specific functions. We show that marrow Tregs are migratory and home back to the marrow.

Intestinal microbiota-derived short-chain fatty acids regulation of immune cell IL-22 production and gut immunity.

Innate lymphoid cells (ILCs) and CD4 T cells produce IL-22, which is critical for intestinal immunity. The microbiota is central to IL-22 production in the intestines; however, the factors that regulate IL-22 production by CD4 T cells and ILCs are not clear. Here, we show that microbiota-derived short-chain fatty acids (SCFAs) promote IL-22 production by CD4 T cells and ILCs through G-protein receptor 41 (GPR41) and inhibiting histone deacetylase (HDAC).

Cutting Edge: ICOS-Deficient Regulatory T Cells Display Normal Induction of but Readily Downregulate Expression of Foxp3.

The ICOS pathway has been implicated in the development and functions of regulatory T (Treg) cells, including those producing IL-10. Treg cell-derived IL-10 is indispensable for the establishment and maintenance of intestinal immune homeostasis. We examined the possible involvement of the ICOS pathway in the accumulation of murine colonic Foxp3- and/or IL-10-expressing cells.

Intestinal microbiota and the immune system in metabolic diseases.

The intestinal microbiota is comprised of millions of microorganisms that reside in the gastrointestinal tract and consistently interact with the host. Host factors such as diet and disease status affect the composition of the microbiota, while the microbiota itself produces metabolites that can further manipulate host physiology. Dysbiosis of the intestinal microbiota has been characterized in patients with certain metabolic diseases, some of which involve damage to the host intestinal epithelial barrier and alterations in the immune system.

TCR-independent functions of Th17 cells mediated by the synergistic actions of cytokines of the IL-12 and IL-1 families.

The development of Th17 cells is accompanied by the acquisition of responsiveness to both IL-12 and IL-23, cytokines with established roles in the development and/or function of Th1 and Th17 cells, respectively. IL-12 signaling promotes antigen-dependent Th1 differentiation but, in combination with IL-18, allows the antigen-independent perpetuation of Th1 responses. On the other hand, while IL-23 is dispensable for initial commitment to the Th17 lineage, it promotes the pathogenic function of the Th17 cells.

T Cell-Derived IL-10 Impairs Host Resistance to Infection.

Tuberculosis (TB), caused by infection, is a leading cause of mortality and morbidity, causing ∼1.5 million deaths annually. CD4 T cells and several cytokines, such as the Th1 cytokine IFN-γ, are critical in the control of this infection.

Colonization potential to reconstitute a microbe community in patients detected early after fecal microbe transplant for recurrent C. difficile.

Background: Fecal microbiota transplants (FMT) are an effective treatment for patients with gut microbe dysbiosis suffering from recurrent C. difficile infections. To further understand how FMT reconstitutes the patient's gut commensal microbiota, we have analyzed the colonization potential of the donor, recipient and recipient post transplant fecal samples using transplantation in gnotobiotic mice.

Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis.

Th17 cells reactive to the enteric microbiota are central to the pathogenesis of certain types of inflammatory bowel disease. However, Th17 cells display substantial developmental plasticity, such that some progeny of Th17 cell precursors retain a predominantly IL-17A(+) phenotype, whereas others extinguish IL-17 expression and acquire expression of IFN-γ, giving rise to "Th1-like" cells. It remains unclear what role these subsets play in inflammatory bowel disease.

IL-22-producing neutrophils contribute to antimicrobial defense and restitution of colonic epithelial integrity during colitis.

IL-22 plays an important role in mucosal epithelial cell homeostasis. Using a dextran sodium sulfate-induced mouse model of acute colitis, we observed an IL-23-dependent up-regulation of IL-22 in the middle and distal colon at the onset of epithelial cell damage. This heightened IL-22 correlated with an influx of innate immune cells, suggesting an important role in colonic epithelial protection.

Role of TLR2-dependent IL-10 production in the inhibition of the initial IFN-γ T cell response to Porphyromonas gingivalis.

P.g., a Gram-negative bacterium, is one of the main etiological agents of the chronic inflammatory disease, periodontitis.

Reciprocal interactions of the intestinal microbiota and immune system.

The emergence of the adaptive immune system in vertebrates set the stage for evolution of an advanced symbiotic relationship with the intestinal microbiota. The defining features of specificity and memory that characterize adaptive immunity have afforded vertebrates the mechanisms for efficiently tailoring immune responses to diverse types of microbes, whether to promote mutualism or host defence. These same attributes can put the host at risk of immune-mediated diseases that are increasingly linked to the intestinal microbiota.

Acute gastrointestinal infection induces long-lived microbiota-specific T cell responses.

The mammalian gastrointestinal tract contains a large and diverse population of commensal bacteria and is also one of the primary sites of exposure to pathogens. How the immune system perceives commensals in the context of mucosal infection is unclear. Here, we show that during a gastrointestinal infection, tolerance to commensals is lost, and microbiota-specific T cells are activated and differentiate to inflammatory effector cells.

Lineage-specific effects of 1,25-dihydroxyvitamin D(3) on the development of effector CD4 T cells.

Vitamin D deficiency is implicated in autoimmune disease. We therefore evaluated the effects of 1α,25-dihydroxyvitamin D(3) (1,25-D(3)), the active form of vitamin D, on the development of T helper 1 (Th1), Th17, and Th9 cells, which are implicated in the pathogenesis of different types of autoimmunity. 1,25-D(3) compromised the development of Th17 and Th9 cells, including IL-22-expressing cells while simultaneously increasing the frequency of IL-10-competent cells.