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  1. Article ; Online: Myeloid deletion of talin-1 reduces mucosal macrophages and protects mice from colonic inflammation

    Yvonne L. Latour / Kara M. McNamara / Margaret M. Allaman / Daniel P. Barry / Thaddeus M. Smith / Mohammad Asim / Kamery J. Williams / Caroline V. Hawkins / Justin Jacobse / Jeremy A. Goettel / Alberto G. Delgado / M. Blanca Piazuelo / M. Kay Washington / Alain P. Gobert / Keith T. Wilson

    Scientific Reports, Vol 13, Iss 1, Pp 1-

    2023  Volume 11

    Abstract: Abstract The intestinal immune response is crucial in maintaining a healthy gut, but the enhanced migration of macrophages in response to pathogens is a major contributor to disease pathogenesis. Integrins are ubiquitously expressed cellular receptors ... ...

    Abstract Abstract The intestinal immune response is crucial in maintaining a healthy gut, but the enhanced migration of macrophages in response to pathogens is a major contributor to disease pathogenesis. Integrins are ubiquitously expressed cellular receptors that are highly involved in immune cell adhesion to endothelial cells while in the circulation and help facilitate extravasation into tissues. Here we show that specific deletion of the Tln1 gene encoding the protein talin-1, an integrin-activating scaffold protein, from cells of the myeloid lineage using the Lyz2-cre driver mouse reduces epithelial damage, attenuates colitis, downregulates the expression of macrophage markers, decreases the number of differentiated colonic mucosal macrophages, and diminishes the presence of CD68-positive cells in the colonic mucosa of mice infected with the enteric pathogen Citrobacter rodentium. Bone marrow-derived macrophages lacking expression of Tln1 did not exhibit a cell-autonomous phenotype; there was no impaired proinflammatory gene expression, nitric oxide production, phagocytic ability, or surface expression of CD11b, CD86, or major histocompatibility complex II in response to C. rodentium. Thus, we demonstrate that talin-1 plays a role in the manifestation of infectious colitis by increasing mucosal macrophages, with an effect that is independent of macrophage activation.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570 ; 616
    Language English
    Publishing date 2023-12-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Iron deficiency linked to altered bile acid metabolism promotes Helicobacter pylori–induced inflammation–driven gastric carcinogenesis

    Jennifer M. Noto / M. Blanca Piazuelo / Shailja C. Shah / Judith Romero-Gallo / Jessica L. Hart / Chao Di / James D. Carmichael / Alberto G. Delgado / Alese E. Halvorson / Robert A. Greevy / Lydia E. Wroblewski / Ayushi Sharma / Annabelle B. Newton / Margaret M. Allaman / Keith T. Wilson / M. Kay Washington / M. Wade Calcutt / Kevin L. Schey / Bethany P. Cummings /
    Charles R. Flynn / Joseph P. Zackular / Richard M. Peek Jr.

    The Journal of Clinical Investigation, Vol 132, Iss

    2022  Volume 10

    Abstract: Gastric carcinogenesis is mediated by complex interactions among Helicobacter pylori, host, and environmental factors. Here, we demonstrate that H. pylori augmented gastric injury in INS-GAS mice under iron-deficient conditions. Mechanistically, these ... ...

    Abstract Gastric carcinogenesis is mediated by complex interactions among Helicobacter pylori, host, and environmental factors. Here, we demonstrate that H. pylori augmented gastric injury in INS-GAS mice under iron-deficient conditions. Mechanistically, these phenotypes were not driven by alterations in the gastric microbiota; however, discovery-based and targeted metabolomics revealed that bile acids were significantly altered in H. pylori–infected mice with iron deficiency, with significant upregulation of deoxycholic acid (DCA), a carcinogenic bile acid. The severity of gastric injury was further augmented when H. pylori–infected mice were treated with DCA, and, in vitro, DCA increased translocation of the H. pylori oncoprotein CagA into host cells. Conversely, bile acid sequestration attenuated H. pylori–induced injury under conditions of iron deficiency. To translate these findings to human populations, we evaluated the association between bile acid sequestrant use and gastric cancer risk in a large human cohort. Among 416,885 individuals, a significant dose-dependent reduction in risk was associated with cumulative bile acid sequestrant use. Further, expression of the bile acid receptor transmembrane G protein–coupled bile acid receptor 5 (TGR5) paralleled the severity of carcinogenic lesions in humans. These data demonstrate that increased H. pylori–induced injury within the context of iron deficiency is tightly linked to altered bile acid metabolism, which may promote gastric carcinogenesis.
    Keywords Gastroenterology ; Infectious disease ; Medicine ; R
    Language English
    Publishing date 2022-05-01T00:00:00Z
    Publisher American Society for Clinical Investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: The L-Arginine Transporter Solute Carrier Family 7 Member 2 Mediates the Immunopathogenesis of Attaching and Effacing Bacteria.

    Kshipra Singh / Nicole T Al-Greene / Thomas G Verriere / Lori A Coburn / Mohammad Asim / Daniel P Barry / Margaret M Allaman / Dana M Hardbower / Alberto G Delgado / M Blanca Piazuelo / Bruce A Vallance / Alain P Gobert / Keith T Wilson

    PLoS Pathogens, Vol 12, Iss 10, p e

    2016  Volume 1005984

    Abstract: Solute carrier family 7 member 2 (SLC7A2) is an inducible transporter of the semi-essential amino acid L-arginine (L-Arg), which has been implicated in immune responses to pathogens. We assessed the role of SLC7A2 in murine infection with Citrobacter ... ...

    Abstract Solute carrier family 7 member 2 (SLC7A2) is an inducible transporter of the semi-essential amino acid L-arginine (L-Arg), which has been implicated in immune responses to pathogens. We assessed the role of SLC7A2 in murine infection with Citrobacter rodentium, an attaching and effacing enteric pathogen that causes colitis. Induction of SLC7A2 was upregulated in colitis tissues, and localized predominantly to colonic epithelial cells. Compared to wild-type mice, Slc7a2-/-mice infected with C. rodentium had improved survival and decreased weight loss, colon weight, and histologic injury; this was associated with decreased colonic macrophages, dendritic cells, granulocytes, and Th1 and Th17 cells. In infected Slc7a2-/-mice, there were decreased levels of the proinflammatory cytokines G-CSF, TNF-α, IL-1α, IL-1β, and the chemokines CXCL1, CCL2, CCL3, CCL4, CXCL2, and CCL5. In bone marrow chimeras, the recipient genotype drove the colitis phenotype, indicative of the importance of epithelial, rather than myeloid SLC7A2. Mice lacking Slc7a2 exhibited reduced adherence of C. rodentium to the colonic epithelium and decreased expression of Talin-1, a focal adhesion protein involved in the attachment of the bacterium. The importance of SLC7A2 and Talin-1 in the intimate attachment of C. rodentium and induction of inflammatory response was confirmed in vitro, using conditionally-immortalized young adult mouse colon (YAMC) cells with shRNA knockdown of Slc7a2 or Tln1. Inhibition of L-Arg uptake with the competitive inhibitor, L-lysine (L-Lys), also prevented attachment of C. rodentium and chemokine expression. L-Lys and siRNA knockdown confirmed the role of L-Arg and SLC7A2 in human Caco-2 cells co-cultured with enteropathogenic Escherichia coli. Overexpression of SLC7A2 in human embryonic kidney cells increased bacterial adherence and chemokine expression. Taken together, our data indicate that C. rodentium enhances its own pathogenicity by inducing the expression of SLC7A2 to favor its attachment to the epithelium and ...
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2016-10-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: The host protein calprotectin modulates the Helicobacter pylori cag type IV secretion system via zinc sequestration.

    Jennifer A Gaddy / Jana N Radin / John T Loh / M Blanca Piazuelo / Thomas E Kehl-Fie / Alberto G Delgado / Florin T Ilca / Richard M Peek / Timothy L Cover / Walter J Chazin / Eric P Skaar / Holly M Scott Algood

    PLoS Pathogens, Vol 10, Iss 10, p e

    2014  Volume 1004450

    Abstract: Transition metals are necessary for all forms of life including microorganisms, evidenced by the fact that 30% of all proteins are predicted to interact with a metal cofactor. Through a process termed nutritional immunity, the host actively sequesters ... ...

    Abstract Transition metals are necessary for all forms of life including microorganisms, evidenced by the fact that 30% of all proteins are predicted to interact with a metal cofactor. Through a process termed nutritional immunity, the host actively sequesters essential nutrient metals away from invading pathogenic bacteria. Neutrophils participate in this process by producing several metal chelating proteins, including lactoferrin and calprotectin (CP). As neutrophils are an important component of the inflammatory response directed against the bacterium Helicobacter pylori, a major risk factor for gastric cancer, it was hypothesized that CP plays a role in the host response to H. pylori. Utilizing a murine model of H. pylori infection and gastric epithelial cell co-cultures, the role CP plays in modifying H. pylori -host interactions and the function of the cag Type IV Secretion System (cag T4SS) was investigated. This study indicates elevated gastric levels of CP are associated with the infiltration of neutrophils to the H. pylori-infected tissue. When infected with an H. pylori strain harboring a functional cag T4SS, calprotectin-deficient mice exhibited decreased bacterial burdens and a trend toward increased cag T4SS -dependent inflammation compared to wild-type mice. In vitro data demonstrate that culturing H. pylori with sub-inhibitory doses of CP reduces the activity of the cag T4SS and the biogenesis of cag T4SS-associated pili in a zinc-dependent fashion. Taken together, these data indicate that zinc homeostasis plays a role in regulating the proinflammatory activity of the cag T4SS.
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2014-10-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Helicobacter pylori promotes the expression of Krüppel-like factor 5, a mediator of carcinogenesis, in vitro and in vivo.

    Jennifer M Noto / Tinatin Khizanishvili / Rupesh Chaturvedi / M Blanca Piazuelo / Judith Romero-Gallo / Alberto G Delgado / Shradha S Khurana / Johanna C Sierra / Uma S Krishna / Giovanni Suarez / Anne E Powell / James R Goldenring / Robert J Coffey / Vincent W Yang / Pelayo Correa / Jason C Mills / Keith T Wilson / Richard M Peek

    PLoS ONE, Vol 8, Iss 1, p e

    2013  Volume 54344

    Abstract: Helicobacter pylori is the strongest known risk factor for the development of gastric adenocarcinoma. H. pylori expresses a repertoire of virulence factors that increase gastric cancer risk, including the cag pathogenicity island and the vacuolating ... ...

    Abstract Helicobacter pylori is the strongest known risk factor for the development of gastric adenocarcinoma. H. pylori expresses a repertoire of virulence factors that increase gastric cancer risk, including the cag pathogenicity island and the vacuolating cytotoxin (VacA). One host element that promotes carcinogenesis within the gastrointestinal tract is Krüppel-like factor 5 (KLF5), a transcription factor that mediates key cellular functions. To define the role of KLF5 within the context of H. pylori-induced inflammation and injury, human gastric epithelial cells were co-cultured with the wild-type cag(+) H. pylori strain 60190. KLF5 expression was significantly upregulated following co-culture with H. pylori, but increased expression was independent of the cag island or VacA. To translate these findings into an in vivo model, C57BL/6 mice were challenged with the wild-type rodent-adapted cag(+) H. pylori strain PMSS1 or a PMSS1 cagE(-) isogenic mutant. Similar to findings in vitro, KLF5 staining was significantly enhanced in gastric epithelium of H. pylori-infected compared to uninfected mice and this was independent of the cag island. Flow cytometry revealed that the majority of KLF5(+) cells also stained positively for the stem cell marker, Lrig1, and KLF5(+)/Lrig1(+) cells were significantly increased in H. pylori-infected versus uninfected tissue. To extend these results into the natural niche of this pathogen, levels of KLF5 expression were assessed in human gastric biopsies isolated from patients with or without premalignant lesions. Levels of KLF5 expression increased in parallel with advancing stages of neoplastic progression, being significantly elevated in gastritis, intestinal metaplasia, and dysplasia compared to normal gastric tissue. These results indicate that H. pylori induces expression of KLF5 in gastric epithelial cells in vitro and in vivo, and that the degree of KLF5 expression parallels the severity of premalignant lesions in human gastric carcinogenesis.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Effect of smoking on failure of H. pylori therapy and gastric histology in a high gastric cancer risk area of Colombia

    M Constanza Camargo / M Blanca Piazuelo / Robertino M Mera / Elizabeth TH Fontham / Alberto G Delgado / M Clara Yepez / Cristina Ceron / Luis E Bravo / Juan C Bravo / Pelayo Correa

    Acta Gastroenterológica Latinoamericana, Vol 37, Iss 4, Pp 238-

    2007  Volume 245

    Abstract: La erradicación del Helicobacter pylori ha sido propuesta como medida promisoria en la prevención del cáncer gástrico. Varios factores, incluyendo el tabaquismo, se asocian con la falla del tratamiento. El objetivo de este estudio fue evaluar el efecto ... ...

    Abstract La erradicación del Helicobacter pylori ha sido propuesta como medida promisoria en la prevención del cáncer gástrico. Varios factores, incluyendo el tabaquismo, se asocian con la falla del tratamiento. El objetivo de este estudio fue evaluar el efecto del tabaquismo en la eficacia del tratamiento anti-H. pylori y en la histología gástrica en residentes de una zona de alto riesgo de cáncer gástrico. Este estudio incluyó 264 sujetos colombianos con lesiones gástricas preneoplásicas que participaron en un estudio de quimioprevención, recibieron tratamiento anti-H. pylori al ingreso, y proveyeron información sobre tabaquismo. Se realizó un detallado análisis histopatológico en las biopsias colectadas al ingreso. La erradicación de la infección fue evaluada en las biopsias gástricas a los 36 meses post-tratamiento. El porcentaje general de erradicación fue de 52.3%, con proporciones de 41.3% y 57.1% en fumadores activos y no fumadores, respectivamente. El análisis de regresión logística múltiple mostró que el riesgo de presentar falla al tratamiento fue doble en fumadores en comparación con los no fumadores (OR: 2.0; 95% CI: 1.01-3.95). Los fumadores presentaron un mayor índice de metaplasia intestinal comparado con los no fumadores. En la mucosa del cuerpo gástrico los fumadores mostraron menores índices de colonización por H. pylori, inflamación total, infiltración de neutrófilos y depleción de moco que los no fumadores. En el antro no se observaron diferencias significacomtivas entre ambos grupos. En conclusión, el tratamiento anti-H. pylori fue menos efectivo en sujetos fumadores. La cesación del consumo de tabaco puede beneficiar las tasas de erradicación del H. pylori.
    Keywords Diseases of the digestive system. Gastroenterology ; RC799-869 ; Specialties of internal medicine ; RC581-951 ; Internal medicine ; RC31-1245 ; Medicine ; R
    Language Spanish
    Publishing date 2007-01-01T00:00:00Z
    Publisher Sociedad Argentina de Gastroenterología
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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