Blair Fennimore

Hypoxia-inducible factor-dependent regulation of platelet-activating factor receptor as a route for gram-positive bacterial translocation across epithelia.

Results from these studies reveal that some strains of Gram-positive bacteria exploit hypoxia-inducible factor-regulated platelet-activating factor receptor as a means for translocation through intestinal epithelial cells.

Adenosine and gastrointestinal inflammation

Nucleosides such as adenosine (Ado) influence nearly every aspect of physiology and pathophysiology. Extracellular nucleotides liberated at local sites of inflammation are metabolized through regulated phosphohydrolysis by a series of ecto-nucleotidases including ectonucleoside triphosphate diphosphohydrolase-1 (CD39) and ecto-5′-nucleotidase (CD73), found on the surface of a variety of cell types. Once generated, Ado is made available to bind and activate one of four G protein-coupled Ado receptors. Recent in vitro and in vivo studies implicate Ado in a broad array of tissue-protective mechanisms that provide new insight into adenosine actions. Studies in cultured cells and murine tissues have indicated that Ado receptors couple to novel posttranslational protein modifications, including Cullin deneddylation, as a new anti-inflammatory mechanism. Studies in Ado receptor-null mice have been revealing and indicate a particularly important role for the Ado A2B receptor in animal models of intestinal inflammation. Here, we review contributions of Ado to cell and tissue stress responses, with a particular emphasis on the gastrointestinal mucosa.

HIF-dependent regulation of AKAP12 (gravin) in the control of human vascular endothelial function

Hypoxia has been widely implicated in many pathological conditions, including those associated with inflammation and tumorigenesis. A number of recent studies have implicated hypoxia in the control of vasculogenesis and permeability, the basis for which is not fully understood. Here we examine the transcriptional regulation of angiogenesis and permeability by hypoxia in endothelial cells. Guided by a global profiling approach in cultured endothelial cells, these studies revealed the selective induction of human gravin (protein kinase A anchoring protein 12) by hypoxia. Analysis of the cloned gravin promoter identified a functional hypoxia‐responsive region including 2 binding sites for hypoxia‐inducible factor (HIF). Site‐directed mutagenesis identified the most distal HIF‐binding site as essential for the induction of gravin by hypoxia. Further studies examining gravin gain and loss of function confirmed strong dependence of gravin in control of microvascular endothelial tube formation, wherein gravin functions as a “braking” system for angiogenesis. Additional studies in confluent endothelia revealed that gravin functionally couples to control endothelial barrier function in response to protein kinase A (PKA) agonists. Taken together, these results demonstrate transcriptional coordination of gravin by HIF‐1α and amplified PKA‐dependent endothelial responses. These findings provide an important link between hypoxia and metabolic conditions associated with inflammation and angiogenesis.—Weissmüller, T., Glover, L. E., Fennimore, B., Curtis, V. F., MacManus, C. F., Ehrentraut, S. F., Campbell, E. L., Scully, M., Grove, B. D., Colgan, S. P. HIF‐dependent regulation of AKAP12 (gravin) in the control of human vascular endothelial function. FASEB J. 28, 256–264 (2014). www.fasebj.org

Inflammatory Bowel Disease: Influence and Implications in Reproduction.

Abstract:The incidence and prevalence of inflammatory bowel disease (IBD) continues to rise with time, signifying its emergence as a global disease. Clinical onset of IBD, comprising Crohns disease and ulcerative colitis, typically occurs before or at peak reproductive age. Although active disease in female patients is associated with reduced fertility and adverse obstetric outcomes in pregnancy, the molecular mechanisms underlying this altered reproductive course, and its impact on IBD transmission to offspring, remain poorly understood. Clinical and experimental studies have now begun to elucidate the hormonal, environmental, and microbial factors that modulate immune-reproductive cross talk in IBD and define their impact on maternal health, fetal development, and heritability of disease risk. Evolving insight into maternal–fetal imprinting in IBD has important implications for patient counseling and disease management during pregnancy and may help predict clinical outcomes for both mother and child.

Functional intraepithelial lymphocyte changes in inflammatory bowel disease and spondyloarthritis have disease specific correlations with intestinal microbiota

BackgroundDysbiosis occurs in spondyloarthritis (SpA) and inflammatory bowel disease (IBD), which is subdivided into Crohn’s disease (CD) and ulcerative colitis (UC). The immunologic consequences of alterations in microbiota, however, have not been defined. Intraepithelial lymphocytes (IELs) are T cells within the intestinal epithelium that are in close contact with bacteria and are likely to be modulated by changes in microbiota. We examined differences in human gut-associated bacteria and tested correlation with functional changes in IELs in patients with axial SpA (axSpA), CD, or UC, and in controls.MethodsWe conducted a case-control study to evaluate IELs from pinch biopsies of grossly normal colonic tissue from subjects with biopsy-proven CD or UC, axSpA fulfilling Assessment of SpondyloArthritis International Society (ASAS) criteria and from controls during endoscopy. IELs were harvested and characterized by flow cytometry for cell surface markers. Secreted cytokines were measured by ELISA. Microbiome analysis was by 16S rRNA gene sequencing from rectal swabs. Statistical analyses were performed with the Kruskal-Wallis and Spearman’s rank tests.ResultsThe total number of IELs was significantly decreased in subjects with axSpA compared to those with IBD and controls, likely due to a decrease in TCRβ+ IELs. We found strong, significant negative correlation between peripheral lymphocyte count and IEL number. IELs secreted significantly increased IL-1β in patients with UC, significantly increased IL-17A and IFN-γ in patients with CD, and significantly increased TNF-α in patients with CD and axSpA as compared to other cohorts. For each disease subtype, IELs and IEL-produced cytokines were positively and negatively correlated with the relative abundance of multiple bacterial taxa.ConclusionsOur data indicate differences in IEL function among subjects with axSpA, CD, and UC compared to healthy controls. We propose that the observed correlation between altered microbiota and IEL function in these populations are relevant to the pathogenesis of axSpA and IBD, and discuss possible mechanisms.Trial registrationClinicalTrials.gov, NCT02389075. Registered on 17 March 2015.

Primary Sclerosing Cholangitis-Associated Inflammatory Bowel Disease

Primary sclerosing cholangitis (PSC) is closely associated with inflammatory bowel disease (IBD). Although there is a clear genetic association between PSC and IBD, the underlying pathogenesis linking these diseases remains unclear. Many studies describe PSC-associated IBD (PSC-IBD) as a distinct phenotype characterized by extensive colitis with predominantly right colon inflammation and rectal sparing as well as a dramatically increased risk of colorectal cancer (CRC). The prevention and management of unfavorable outcomes related to colonic dysplasia are key aspects to the care of patients with PSC-IBD. Additional challenges are posed by the management of IBD in the setting of liver transplantation. In summary, PSC-IBD is a common occurrence among PSC patients that presents distinct diagnostic, prognostic, and management issues with additional unique considerations in the posttransplant setting.