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Article: Inflammatory macrophages prevent colonic goblet and enteroendocrine cell differentiation through Notch signaling.

Atanga, Roger / Romero, Aaron S / Hernandez, Anthony Jimenez / Peralta-Herrera, Eduardo / Merkley, Seth D / In, Julie G / Castillo, Eliseo F

bioRxiv : the preprint server for biology

2023

Abstract: Inflammatory macrophages in the intestine are a key pathogenic factor driving inflammatory bowel disease (IBD). Here, we report the role of inflammatory macrophage-mediated notch signaling on secretory lineage differentiation in the intestinal epithelium. ...

Abstract	Inflammatory macrophages in the intestine are a key pathogenic factor driving inflammatory bowel disease (IBD). Here, we report the role of inflammatory macrophage-mediated notch signaling on secretory lineage differentiation in the intestinal epithelium. Utilizing IL-10-deficient (
Language	English
Publishing date	2023-06-29
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.06.29.547119
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Article: Uranium-bearing dust induces differentiation and expansion of enteroendocrine cells in human colonoids.

Atanga, Roger / Appell, Lidia L / Lauer, Fredine T / Brearley, Adrian / Campen, Matthew J / Castillo, Eliseo F / In, Julie G

bioRxiv : the preprint server for biology

2023

Abstract: Chronic exposure to environmental toxins and heavy metals has been associated with intestinal inflammation, increased susceptibility to pathogen-induced diseases, and higher incidences of colorectal cancer, all of which have been steadily increasing in ... ...

Abstract	Chronic exposure to environmental toxins and heavy metals has been associated with intestinal inflammation, increased susceptibility to pathogen-induced diseases, and higher incidences of colorectal cancer, all of which have been steadily increasing in prevalence for the past 40 years. The negative effects of heavy metals on barrier permeability and inhibition of intestinal epithelial healing have been described; however, transcriptomic changes within the intestinal epithelial cells and impacts on lineage differentiation are largely unknown. Uranium exposure remains an important environmental legacy and physiological health concern, with hundreds of abandoned uranium mines located in the Southwestern United States largely impacting underserved indigenous communities. Herein, using human colonoids, we defined the molecular and cellular changes that occur in response to uranium bearing dust (UBD) exposure. We used single cell RNA sequencing to define the molecular changes that occur to specific identities of colonic epithelial cells. We demonstrate that this environmental toxicant disrupts proliferation and induces hyperplastic differentiation of secretory lineage cells, particularly enteroendocrine cells (EEC). EECs respond to UBD exposure with increased differentiation into
Language	English
Publishing date	2023-08-10
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.08.10.552796
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Article ; Online: Integrating 4-D light-sheet fluorescence microscopy and genetic zebrafish system to investigate ambient pollutants-mediated toxicity.

Gonzalez-Ramos, Sheila / Wang, Jing / Cho, Jae Min / Zhu, Enbo / Park, Seul-Ki / In, Julie G / Reddy, Srinivasa T / Castillo, Eliseo F / Campen, Matthew J / Hsiai, Tzung K

The Science of the total environment

2023 Volume 902, Page(s) 165947

Abstract: Ambient air pollutants, including ... ...

Abstract	Ambient air pollutants, including PM
MeSH term(s)	Humans ; Animals ; Zebrafish ; Environmental Pollutants ; Air Pollutants/toxicity ; Air Pollutants/analysis ; Air Pollution/analysis ; Microscopy, Fluorescence/methods ; Particulate Matter/toxicity
Chemical Substances	Environmental Pollutants ; Air Pollutants ; Particulate Matter
Language	English
Publishing date	2023-08-03
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	121506-1
ISSN	1879-1026 ; 0048-9697
ISSN (online)	1879-1026
ISSN	0048-9697
DOI	10.1016/j.scitotenv.2023.165947
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Article ; Online: Orchestration of epithelial-derived cytokines and innate immune cells in allergic airway inflammation.

Castillo, Eliseo F / Zheng, Handong / Yang, Xuexian O

Cytokine & growth factor reviews

2017 Volume 39, Page(s) 19–25

Abstract: Allergic asthma, a chronic respiratory disease, is a leading worldwide health problem, which inflames and constricts the airways, leading to breathing difficulty. Many studies have focused on the pathogenesis contributed by the adaptive immune system, ... ...

Abstract	Allergic asthma, a chronic respiratory disease, is a leading worldwide health problem, which inflames and constricts the airways, leading to breathing difficulty. Many studies have focused on the pathogenesis contributed by the adaptive immune system, including CD4
MeSH term(s)	Animals ; Asthma/immunology ; B-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/immunology ; Cytokines/immunology ; Epithelial Cells/immunology ; Humans ; Hypersensitivity/immunology ; Immunity, Innate ; Inflammation/immunology ; Mice ; Natural Killer T-Cells/immunology ; Th2 Cells/immunology
Chemical Substances	Cytokines
Language	English
Publishing date	2017-11-21
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1330534-7
ISSN	1879-0305 ; 1359-6101
ISSN (online)	1879-0305
ISSN	1359-6101
DOI	10.1016/j.cytogfr.2017.11.004
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Zs.A 2653: Show issues

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Article ; Online: In Vivo

Environmental health perspectives

2024 Volume 132, Issue 4, Page(s) 47005

Abstract: Background: Global plastic use has consistently increased over the past century with several different types of plastics now being produced. Much of these plastics end up in oceans or landfills leading to a substantial accumulation of plastics in the ... ...

Abstract	Background: Global plastic use has consistently increased over the past century with several different types of plastics now being produced. Much of these plastics end up in oceans or landfills leading to a substantial accumulation of plastics in the environment. Plastic debris slowly degrades into microplastics (MPs) that can ultimately be inhaled or ingested by both animals and humans. A growing body of evidence indicates that MPs can cross the gut barrier and enter into the lymphatic and systemic circulation leading to accumulation in tissues such as the lungs, liver, kidney, and brain. The impacts of mixed MPs exposure on tissue function through metabolism remains largely unexplored. Objectives: This study aims to investigate the impacts of polymer microspheres on tissue metabolism in mice by assessing the microspheres ability to translocate across the gut barrier and enter into systemic circulation. Specifically, we wanted to examine microsphere accumulation in different organ systems, identify concentration-dependent metabolic changes, and evaluate the effects of mixed microsphere exposures on health outcomes. Methods: To investigate the impact of ingested microspheres on target metabolic pathways, mice were exposed to either polystyrene ( Results: In mice that ingested microspheres, we detected polystyrene microspheres in distant tissues including the brain, liver, and kidney. Additionally, we report on the metabolic differences that occurred in the colon, liver, and brain, which showed differential responses that were dependent on concentration and type of microsphere exposure. Discussion: This study uses a mouse model to provide critical insight into the potential health implications of the pervasive issue of plastic pollution. These findings demonstrate that orally consumed polystyrene or mixed polymer microspheres can accumulate in tissues such as the brain, liver, and kidney. Furthermore, this study highlights concentration-dependent and polymer type-specific metabolic changes in the colon, liver, and brain after plastic microsphere exposure. These results underline the mobility within and between biological tissues of MPs after exposure and emphasize the importance of understanding their metabolic impact. https://doi.org/10.1289/EHP13435.
MeSH term(s)	Humans ; Animals ; Mice ; Polystyrenes ; Microspheres ; Plastics ; Tissue Distribution ; Microplastics ; Water Pollutants, Chemical/analysis
Chemical Substances	Polystyrenes ; Plastics ; Microplastics ; Water Pollutants, Chemical
Language	English
Publishing date	2024-04-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	195189-0
ISSN	1552-9924 ; 0091-6765 ; 1078-0475
ISSN (online)	1552-9924
ISSN	0091-6765 ; 1078-0475
DOI	10.1289/EHP13435
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Zs.B 1360: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MO 379: Show issues

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Article ; Online: Integrating 4-D light-sheet fluorescence microscopy and genetic zebrafish system to investigate ambient pollutants-mediated toxicity

Gonzalez-Ramos, Sheila / Wang, Jing / Cho, Jae Min / Zhu, Enbo / Park, Seul-Ki / In, Julie G. / Reddy, Srinivasa T. / Castillo, Eliseo F. / Campen, Matthew J. / Hsiai, Tzung K.

Science of the Total Environment. 2023 Aug. 03, p.165947-

2023 , Page(s) 165947–

Abstract: Ambient air pollutants, including PM₂.₅ (aerodynamic diameter d ~2.5 μm), PM₁₀ (d ~10 μm), and ultrafine particles (UFP: d < 0.1 μm) impart both short- and long-term toxicity to various organs, including cardiopulmonary, central nervous, and ... ...

Abstract	Ambient air pollutants, including PM₂.₅ (aerodynamic diameter d ~2.5 μm), PM₁₀ (d ~10 μm), and ultrafine particles (UFP: d < 0.1 μm) impart both short- and long-term toxicity to various organs, including cardiopulmonary, central nervous, and gastrointestinal systems. While rodents have been the principal animal model to elucidate air pollution-mediated organ dysfunction, zebrafish (Danio rerio) is genetically tractable for its short husbandry and life cycle to study ambient pollutants. Its electrocardiogram (ECG) resembles that of humans, and the fluorescent reporter-labeled tissues in the zebrafish system allow for screening a host of ambient pollutants that impair cardiovascular development, organ regeneration, and gut-vascular barriers. In parallel, the high spatiotemporal resolution of light-sheet fluorescence microscopy (LSFM) enables investigators to take advantage of the transparent zebrafish embryos and genetically labeled fluorescent reporters for imaging the dynamic cardiac structure and function at a single-cell resolution. In this context, our review highlights the integrated strengths of the genetic zebrafish system and LSFM for high-resolution and high-throughput investigation of ambient pollutants-mediated cardiac and intestinal toxicity.
Keywords	Danio rerio ; aerodynamics ; air ; animal models ; electrocardiography ; environment ; fluorescence ; fluorescence microscopy ; intestines ; toxicity ; Ultrafine particles ; Zebrafish ; Cardiovascular health ; Gastrointestinal health ; Light-sheet fluorescence microscopy
Language	English
Dates of publication	2023-0803
Publishing place	Elsevier B.V.
Document type	Article ; Online
Note	Pre-press version
ZDB-ID	121506-1
ISSN	1879-1026 ; 0048-9697
ISSN (online)	1879-1026
ISSN	0048-9697
DOI	10.1016/j.scitotenv.2023.165947
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Article ; Online: Matrix Metalloproteinase MMP-12 Promotes Macrophage Transmigration Across Intestinal Epithelial Tight Junctions and Increases Severity of Experimental Colitis.

Nighot, Meghali / Ganapathy, Ashwinkumar Subramenium / Saha, Kushal / Suchanec, Eric / Castillo, Eliseo F / Gregory, Alyssa / Shapiro, Steven / Ma, Thomas / Nighot, Prashant

Journal of Crohn's & colitis

2021 Volume 15, Issue 10, Page(s) 1751–1765

Abstract: Background and aims: Matrix metalloproteinases [MMPs] play an important role in extracellular matrix regulation during cell growth and wound healing. Increased expression of MMP-12 [human macrophage elastase] has been reported in inflammatory bowel ... ...

Abstract	Background and aims: Matrix metalloproteinases [MMPs] play an important role in extracellular matrix regulation during cell growth and wound healing. Increased expression of MMP-12 [human macrophage elastase] has been reported in inflammatory bowel disease [IBD] which is characterised by the loss of epithelial tight junction [TJ] barrier function and an excessive inflammatory response. The aim of this study was to investigate the role of MMP-12 in intestinal TJ barrier function and inflammation. Methods: Wild type [WT] and MMP-12-/- mice were subjected to experimental acute or chronic dextran sodium sulphate [DSS] colitis. The mouse colonic permeability was measured in vivo by recycling perfusion of the entire colon and ex vivo by Ussing chamber studies. Results: DSS administration increased colonic permeability through modulation of TJ proteins and also increased MMP-12 expression in the colonic mucosa of WT mice. The acute as well as chronic DSS-induced increase in colonic TJ permeability and the severity of DSS colitis was found to be markedly attenuated in MMP-12-/- mice. The resistance of MMP-12-/- mice to DSS colitis was characterised by reduced macrophage infiltration and transmigration, and reduced basement membrane laminin degradation. Further in vitro and in vivo studies show that macrophage transmigration across the epithelial layer is MMP-12 dependent and the epithelial TJ barrier is compromised during macrophage transmigration. Conclusions: Together, these data demonstrate that MMP-12 mediated degradation of basement membrane laminin, macrophage transmigration, and associated loss of intestinal TJ barrier are key pathogenic factors for intestinal inflammation.
MeSH term(s)	Animals ; Basement Membrane/pathology ; Cell Movement ; Colitis/metabolism ; Colitis/pathology ; Disease Models, Animal ; Intestinal Mucosa/metabolism ; Intestinal Mucosa/pathology ; Macrophages/metabolism ; Matrix Metalloproteinase 12/metabolism ; Mice, Knockout ; Severity of Illness Index ; Tight Junctions/physiology ; Mice
Chemical Substances	Matrix Metalloproteinase 12 (EC 3.4.24.65) ; matrix metallopeptidase 12, mouse (EC 3.4.24.65)
Language	English
Publishing date	2021-04-09
Publishing country	England
Document type	Journal Article
ZDB-ID	2390120-2
ISSN	1876-4479 ; 1873-9946
ISSN (online)	1876-4479
ISSN	1873-9946
DOI	10.1093/ecco-jcc/jjab064
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Article: MK2: an unrecognized regulator of tumor promoting macrophages in colorectal cancer?

Castillo, Eliseo F / Ray, Anita L / Beswick, Ellen J

Macrophage

2016 Volume 3

Abstract: Colorectal cancer (CRC) is one of the most common malignancies and is associated closely with inflammation before and after development. Macrophages promote colitis and colitis-associated CRC. M1 macrophages contribute to colitis directly through the ... ...

Abstract	Colorectal cancer (CRC) is one of the most common malignancies and is associated closely with inflammation before and after development. Macrophages promote colitis and colitis-associated CRC. M1 macrophages contribute to colitis directly through the production of proinflammatory cytokines and through activation of proinflammatory immune cell phenotypes. In cancer, both M1 and M2 macrophages participate in tumor development and progression through cytokine production, changes in cell signaling and activation of T cells. We have identified the mitogen-activated protein kinase-activated protein kinase 2 (MK2) as a regulator of macrophages during colitis-associated CRC (CAC). MK2 is a proinflammatory kinase that promotes production of IL-1α, IL-1β, IL-6 and TNF-α. MK2
Language	English
Publishing date	2016-02-01
Publishing country	United States
Document type	Journal Article
ISSN	2378-136X
ISSN	2378-136X
DOI	10.14800/macrophage.1166
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Article ; Online: Exposures to uranium and arsenic alter intraepithelial and innate immune cells in the small intestine of male and female mice.

Medina, Sebastian / Lauer, Fredine T / Castillo, Eliseo F / Bolt, Alicia M / Ali, Abdul-Mehdi S / Liu, Ke Jian / Burchiel, Scott W

Toxicology and applied pharmacology

2020 Volume 403, Page(s) 115155

Abstract: Human exposures to environmental metals, including uranium (U) and arsenic (As) are a global public health concern. Chronic exposures to U and As are linked to many adverse health effects including, immune suppression and autoimmunity. The ... ...

Abstract	Human exposures to environmental metals, including uranium (U) and arsenic (As) are a global public health concern. Chronic exposures to U and As are linked to many adverse health effects including, immune suppression and autoimmunity. The gastrointestinal (GI) tract is home to many immune cells vital in the maintenance of systemic immune health. However, very little is known about the immunotoxicity of U and As at this site. The present study examined the burden of U and As exposure in the GI tract as well as the resultant immunotoxicity to intraepithelial lymphocytes (IELs) and innate immune cells of the small intestine following chronic drinking water exposures of male and female mice to U (in the form of uranyl acetate, UA) and As (in the form of sodium arsenite, As
MeSH term(s)	Administration, Oral ; Animals ; Arsenic/toxicity ; Drinking Water ; Female ; Immunity, Innate/drug effects ; Intestine, Small/cytology ; Intestine, Small/drug effects ; Male ; Mice ; Mice, Inbred C57BL ; Sex Factors ; Uranium/toxicity
Chemical Substances	Drinking Water ; Uranium (4OC371KSTK) ; Arsenic (N712M78A8G)
Language	English
Publishing date	2020-07-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	204477-8
ISSN	1096-0333 ; 0041-008X
ISSN (online)	1096-0333
ISSN	0041-008X
DOI	10.1016/j.taap.2020.115155
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Zs.B 14: Show issues

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Article: In Vivo Tissue Distribution of Microplastics and Systemic Metabolomic Alterations After Gastrointestinal Exposure.

bioRxiv : the preprint server for biology

2023

Abstract: Global plastic use has consistently increased over the past century with several different types of plastics now being produced. Much of these plastics end up in oceans or landfills leading to a substantial accumulation of plastics in the environment. ... ...

Abstract	Global plastic use has consistently increased over the past century with several different types of plastics now being produced. Much of these plastics end up in oceans or landfills leading to a substantial accumulation of plastics in the environment. Plastic debris slowly degrades into microplastics (MPs) that can ultimately be inhaled or ingested by both animals and humans. A growing body of evidence indicates that MPs can cross the gut barrier and enter into the lymphatic and systemic circulation leading to accumulation in tissues such as the lungs, liver, kidney, and brain. The impacts of mixed MPs exposure on tissue function through metabolism remains largely unexplored. To investigate the impact of ingested MPs on target metabolomic pathways, mice were subjected to either polystyrene microspheres or a mixed plastics (5 µm) exposure consisting of polystyrene, polyethylene and the biodegradability and biocompatible plastic, poly-(lactic-co-glycolic acid). Exposures were performed twice a week for four weeks at a dose of either 0, 2, or 4 mg/week via oral gastric gavage. Our findings demonstrate that, in mice, ingested MPs can pass through the gut barrier, be translocated through the systemic circulation, and accumulate in distant tissues including the brain, liver, and kidney. Additionally, we report on the metabolomic changes that occur in the colon, liver and brain which show differential responses that are dependent on dose and type of MPs exposure. Lastly, our study provides proof of concept for identifying metabolomic alterations associated with MPs exposure and adds insight into the potential health risks that mixed MPs contamination may pose to humans.
Language	English
Publishing date	2023-06-03
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.06.02.542598
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