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Article ; Online: SELENOP modifies sporadic colorectal carcinogenesis and WNT signaling activity through LRP5/6 interactions

Jennifer M. Pilat / Rachel E. Brown / Zhengyi Chen / Nathaniel J. Berle / Adrian P. Othon / M. Kay Washington / Shruti A. Anant / Suguru Kurokawa / Victoria H. Ng / Joshua J. Thompson / Justin Jacobse / Jeremy A. Goettel / Ethan Lee / Yash A. Choksi / Ken S. Lau / Sarah P. Short / Christopher S. Williams

The Journal of Clinical Investigation, Vol 133, Iss

2023 Volume 13

Abstract: Although selenium deficiency correlates with colorectal cancer (CRC) risk, the roles of the selenium-rich antioxidant selenoprotein P (SELENOP) in CRC remain unclear. In this study, we defined SELENOP’s contributions to sporadic CRC. In human single-cell ...

Abstract	Although selenium deficiency correlates with colorectal cancer (CRC) risk, the roles of the selenium-rich antioxidant selenoprotein P (SELENOP) in CRC remain unclear. In this study, we defined SELENOP’s contributions to sporadic CRC. In human single-cell cRNA-Seq (scRNA-Seq) data sets, we discovered that SELENOP expression rose as normal colon stem cells transformed into adenomas that progressed into carcinomas. We next examined the effects of Selenop KO in a mouse adenoma model that involved conditional, intestinal epithelium-specific deletion of the tumor suppressor adenomatous polyposis coli (Apc) and found that Selenop KO decreased colon tumor incidence and size. We mechanistically interrogated SELENOP-driven phenotypes in tumor organoids as well as in CRC and noncancer cell lines. Selenop-KO tumor organoids demonstrated defects in organoid formation and decreases in WNT target gene expression, which could be reversed by SELENOP restoration. Moreover, SELENOP increased canonical WNT signaling activity in noncancer and CRC cell lines. In defining the mechanism of action of SELENOP, we mapped protein-protein interactions between SELENOP and the WNT coreceptors low-density lipoprotein receptor–related proteins 5 and 6 (LRP5/6). Last, we confirmed that SELENOP-LRP5/6 interactions contributed to the effects of SELENOP on WNT activity. Overall, our results position SELENOP as a modulator of the WNT signaling pathway in sporadic CRC.
Keywords	Gastroenterology ; Medicine ; R
Subject code	570
Language	English
Publishing date	2023-07-01T00:00:00Z
Publisher	American Society for Clinical Investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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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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Article ; Online: MTG16 regulates colonic epithelial differentiation, colitis, and tumorigenesis by repressing E protein transcription factors

JCI Insight, Vol 7, Iss

2022 Volume 10

Abstract: Aberrant epithelial differentiation and regeneration contribute to colon pathologies, including inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Myeloid translocation gene 16 (MTG16, also known as CBFA2T3) is a transcriptional ... ...

Abstract	Aberrant epithelial differentiation and regeneration contribute to colon pathologies, including inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Myeloid translocation gene 16 (MTG16, also known as CBFA2T3) is a transcriptional corepressor expressed in the colonic epithelium. MTG16 deficiency in mice exacerbates colitis and increases tumor burden in CAC, though the underlying mechanisms remain unclear. Here, we identified MTG16 as a central mediator of epithelial differentiation, promoting goblet and restraining enteroendocrine cell development in homeostasis and enabling regeneration following dextran sulfate sodium–induced (DSS-induced) colitis. Transcriptomic analyses implicated increased Ephrussi box–binding transcription factor (E protein) activity in MTG16-deficient colon crypts. Using a mouse model with a point mutation that attenuates MTG16:E protein interactions (Mtg16P209T), we showed that MTG16 exerts control over colonic epithelial differentiation and regeneration by repressing E protein–mediated transcription. Mimicking murine colitis, MTG16 expression was increased in biopsies from patients with active IBD compared with unaffected controls. Finally, uncoupling MTG16:E protein interactions partially phenocopied the enhanced tumorigenicity of Mtg16–/– colon in the azoxymethane/DSS-induced model of CAC, indicating that MTG16 protects from tumorigenesis through additional mechanisms. Collectively, our results demonstrate that MTG16, via its repression of E protein targets, is a key regulator of cell fate decisions during colon homeostasis, colitis, and cancer.
Keywords	Cell biology ; Gastroenterology ; Medicine ; R
Subject code	570
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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Article ; Online: Interleukin-23 receptor signaling impairs the stability and function of colonic regulatory T cells

Justin Jacobse / Rachel E. Brown / Jing Li / Jennifer M. Pilat / Ly Pham / Sarah P. Short / Christopher T. Peek / Andrea Rolong / M. Kay Washington / Ruben Martinez-Barricarte / Mariana X. Byndloss / Catherine Shelton / Janet G. Markle / Yvonne L. Latour / Margaret M. Allaman / James E. Cassat / Keith T. Wilson / Yash A. Choksi / Christopher S. Williams /

Ken S. Lau / Charles R. Flynn / Jean-Laurent Casanova / Edmond H.H.M. Rings / Janneke N. Samsom / Jeremy A. Goettel

Cell Reports, Vol 42, Iss 2, Pp 112128- (2023)

2023

Abstract: Summary: The cytokine interleukin-23 (IL-23) is involved in the pathogenesis of inflammatory and autoimmune conditions including inflammatory bowel disease (IBD). IL23R is enriched in intestinal Tregs, yet whether IL-23 modulates intestinal Tregs remains ...

Abstract	Summary: The cytokine interleukin-23 (IL-23) is involved in the pathogenesis of inflammatory and autoimmune conditions including inflammatory bowel disease (IBD). IL23R is enriched in intestinal Tregs, yet whether IL-23 modulates intestinal Tregs remains unknown. Here, investigating IL-23R signaling in Tregs specifically, we show that colonic Tregs highly express Il23r compared with Tregs from other compartments and their frequency is reduced upon IL-23 administration and impairs Treg suppressive function. Similarly, colonic Treg frequency is increased in mice lacking Il23r specifically in Tregs and exhibits a competitive advantage over IL-23R-sufficient Tregs during inflammation. Finally, IL-23 antagonizes liver X receptor pathway, cellular cholesterol transporter Abca1, and increases Treg apoptosis. Our results show that IL-23R signaling regulates intestinal Tregs by increasing cell turnover, antagonizing suppression, and decreasing cholesterol efflux. These results suggest that IL-23 negatively regulates Tregs in the intestine with potential implications for promoting chronic inflammation in patients with IBD.
Keywords	CP: Immunology ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2023-02-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Utilizing a reductionist model to study host-microbe interactions in intestinal inflammation

Microbiome, Vol 9, Iss 1, Pp 1-

2021 Volume 17

Abstract: Abstract Background The gut microbiome is altered in patients with inflammatory bowel disease, yet how these alterations contribute to intestinal inflammation is poorly understood. Murine models have demonstrated the importance of the microbiome in ... ...

Abstract	Abstract Background The gut microbiome is altered in patients with inflammatory bowel disease, yet how these alterations contribute to intestinal inflammation is poorly understood. Murine models have demonstrated the importance of the microbiome in colitis since colitis fails to develop in many genetically susceptible animal models when re-derived into germ-free environments. We have previously shown that Wiskott-Aldrich syndrome protein (WASP)-deficient mice (Was −/− ) develop spontaneous colitis, similar to human patients with loss-of-function mutations in WAS. Furthermore, we showed that the development of colitis in Was −/− mice is Helicobacter dependent. Here, we utilized a reductionist model coupled with multi-omics approaches to study the role of host-microbe interactions in intestinal inflammation. Results Was −/− mice colonized with both altered Schaedler flora (ASF) and Helicobacter developed colitis, while those colonized with either ASF or Helicobacter alone did not. In Was −/− mice, Helicobacter relative abundance was positively correlated with fecal lipocalin-2 (LCN2), a marker of intestinal inflammation. In contrast, WT mice colonized with ASF and Helicobacter were free of inflammation and strikingly, Helicobacter relative abundance was negatively correlated with LCN2. In Was −/− colons, bacteria breach the mucus layer, and the mucosal relative abundance of ASF457 Mucispirillum schaedleri was positively correlated with fecal LCN2. Meta-transcriptomic analyses revealed that ASF457 had higher expression of genes predicted to enhance fitness and immunogenicity in Was −/− compared to WT mice. In contrast, ASF519 Parabacteroides goldsteinii’s relative abundance was negatively correlated with LCN2 in Was −/− mice, and transcriptional analyses showed lower expression of genes predicted to facilitate stress adaptation by ASF519 in Was −/− compared to WT mice. Conclusions These studies indicate that the effect of a microbe on the immune system can be context dependent, with the same bacteria eliciting a ...
Keywords	Intestinal inflammation ; Wiskott-Aldrich syndrome ; Immune dysregulation ; Gut microbiota ; Defined consortium ; Pathobiont ; Microbial ecology ; QR100-130
Subject code	570
Language	English
Publishing date	2021-11-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: AHR Activation Is Protective against Colitis Driven by T Cells in Humanized Mice

Jeremy A. Goettel / Roopali Gandhi / Jessica E. Kenison / Ada Yeste / Gopal Murugaiyan / Sharmila Sambanthamoorthy / Alexandra E. Griffith / Bonny Patel / Dror S. Shouval / Howard L. Weiner / Scott B. Snapper / Francisco J. Quintana

Cell Reports, Vol 17, Iss 5, Pp 1318-

2016 Volume 1329

Abstract: Summary: Existing therapies for inflammatory bowel disease that are based on broad suppression of inflammation result in variable clinical benefit and unwanted side effects. A potential therapeutic approach for promoting immune tolerance is the in vivo ... ...

Abstract	Summary: Existing therapies for inflammatory bowel disease that are based on broad suppression of inflammation result in variable clinical benefit and unwanted side effects. A potential therapeutic approach for promoting immune tolerance is the in vivo induction of regulatory T cells (Tregs). Here we report that activation of the aryl hydrocarbon receptor using the non-toxic agonist 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) induces human Tregs in vitro that suppress effector T cells through a mechanism mediated by CD39 and Granzyme B. We then developed a humanized murine system whereby human CD4+ T cells drive colitis upon exposure to 2,4,6-trinitrobenzenesulfonic acid and assessed ITE as a potential therapeutic. ITE administration ameliorated colitis in humanized mice with increased CD39, Granzyme B, and IL10-secreting human Tregs. These results develop an experimental model to investigate human CD4+ T responses in vivo and identify the non-toxic AHR agonist ITE as a potential therapy for promoting immune tolerance in the intestine. : Therapeutic approaches aimed at expanding regulatory T cells in the gut to promote immune tolerance in patients with inflammatory bowel disease (IBD) are of clinical significance. Goettel et al. establish a humanized murine model of IBD driven by human T cells and find that activation of AHR by the non-toxic agonist ITE can prevent experimental colitis. Keywords: AHR, treg, humanized mice, IBD, ITE
Keywords	Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2016-10-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: WASP-mediated regulation of anti-inflammatory macrophages is IL-10 dependent and is critical for intestinal homeostasis

Amlan Biswas / Dror S. Shouval / Alexandra Griffith / Jeremy A. Goettel / Michael Field / Yu Hui Kang / Liza Konnikova / Erin Janssen / Naresh Singh Redhu / Adrian J. Thrasher / Talal Chatila / Vijay K. Kuchroo / Raif S Geha / Luigi D. Notarangelo / Sung-Yun Pai / Bruce H. Horwitz / Scott B. Snapper

Nature Communications, Vol 9, Iss 1, Pp 1-

2018 Volume 15

Abstract: Deficiency in Wiskott-Aldrich syndrome protein (WASP) has been associated with autoimmune colitis, but the underlying mechanism is still unclear. Here the authors show that WASP deficiency is associated with defective WASP/DOCK8 complex formation, ... ...

Abstract	Deficiency in Wiskott-Aldrich syndrome protein (WASP) has been associated with autoimmune colitis, but the underlying mechanism is still unclear. Here the authors show that WASP deficiency is associated with defective WASP/DOCK8 complex formation, altered IL-10 signalling, and impaired anti-inflammatory macrophage functions.
Keywords	Science ; Q
Language	English
Publishing date	2018-05-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Alpha kinase 1 controls intestinal inflammation by suppressing the IL-12/Th1 axis

Grigory Ryzhakov / Nathaniel R. West / Fanny Franchini / Simon Clare / Nicholas E. Ilott / Stephen N. Sansom / Samuel J. Bullers / Claire Pearson / Alice Costain / Alun Vaughan-Jackson / Jeremy A. Goettel / Joerg Ermann / Bruce H. Horwitz / Ludovico Buti / Xin Lu / Subhankar Mukhopadhyay / Scott B. Snapper / Fiona Powrie

Nature Communications, Vol 9, Iss 1, Pp 1-

2018 Volume 13

Abstract: The Hiccs locus has been associated with susceptibility to colitis in mice. Here the authors identify a Hiccs locus gene encoding Alpha kinase 1 as a potent regulator of intestinal inflammation via modulation of the IL-12/Th1 axis. ...

Abstract	The Hiccs locus has been associated with susceptibility to colitis in mice. Here the authors identify a Hiccs locus gene encoding Alpha kinase 1 as a potent regulator of intestinal inflammation via modulation of the IL-12/Th1 axis.
Keywords	Science ; Q
Language	English
Publishing date	2018-09-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: WASP-mediated regulation of anti-inflammatory macrophages is IL-10 dependent and is critical for intestinal homeostasis

Nature Communications, Vol 9, Iss 1, Pp 1-

2018 Volume 15

Abstract	Deficiency in Wiskott-Aldrich syndrome protein (WASP) has been associated with autoimmune colitis, but the underlying mechanism is still unclear. Here the authors show that WASP deficiency is associated with defective WASP/DOCK8 complex formation, altered IL-10 signalling, and impaired anti-inflammatory macrophage functions.
Keywords	Science ; Q
Language	English
Publishing date	2018-05-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Macrophage dysfunction initiates colitis during weaning of infant mice lacking the interleukin-10 receptor

Naresh S Redhu / Vasudevan Bakthavatchalu / Evan A Conaway / Dror S Shouval / Amy Tsou / Jeremy A Goettel / Amlan Biswas / Chuanwu Wang / Michael Field / Werner Muller / Andre Bleich / Ning Li / Georg K Gerber / Lynn Bry / James G Fox / Scott B Snapper / Bruce H Horwitz

eLife, Vol

2017 Volume 6

Abstract: Infants with defects in the interleukin 10 receptor (IL10R) develop very early onset inflammatory bowel disease. Whether IL10R regulates lamina propria macrophage function during infant development in mice and whether macrophage-intrinsic IL10R signaling ...

Abstract	Infants with defects in the interleukin 10 receptor (IL10R) develop very early onset inflammatory bowel disease. Whether IL10R regulates lamina propria macrophage function during infant development in mice and whether macrophage-intrinsic IL10R signaling is required to prevent colitis in infancy is unknown. Here we show that although signs of colitis are absent in IL10R-deficient mice during the first two weeks of life, intestinal inflammation and macrophage dysfunction begin during the third week of life, concomitant with weaning and accompanying diversification of the intestinal microbiota. However, IL10R did not directly regulate the microbial ecology during infant development. Interestingly, macrophage depletion with clodronate inhibited the development of colitis, while the absence of IL10R specifically on macrophages sensitized infant mice to the development of colitis. These results indicate that IL10R-mediated regulation of macrophage function during the early postnatal period is indispensable for preventing the development of murine colitis.
Keywords	inflammatory bowel disease ; infant ; Interleukin 10 ; Interleukin 10 receptor ; macrophage ; intestine ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2017-07-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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