Loss of H2R Signaling Disrupts Neutrophil Homeostasis and Promotes Inflammation-Associated Colonic Tumorigenesis in MiceSummary
Background & Aims: We previously showed that histamine suppressed inflammation-associated colonic tumorigenesis through histamine type 2 receptor (H2R) signaling in mice. This study aimed to precisely elucidate the downstream effects of H2R activation in innate immune cells. Methods: Analyse...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X2100237X |
| _version_ | 1819289162762682368 |
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| author | Zhongcheng Shi, PhD Yuko Mori-Akiyama, MD Wa Du, PhD Robert Fultz, PhD Yanling Zhao, PhD Wenly Ruan, MD Susan Venable Melinda A. Engevik, PhD James Versalovic, MD, PhD |
| author_facet | Zhongcheng Shi, PhD Yuko Mori-Akiyama, MD Wa Du, PhD Robert Fultz, PhD Yanling Zhao, PhD Wenly Ruan, MD Susan Venable Melinda A. Engevik, PhD James Versalovic, MD, PhD |
| author_sort | Zhongcheng Shi, PhD |
| collection | DOAJ |
| description | Background & Aims: We previously showed that histamine suppressed inflammation-associated colonic tumorigenesis through histamine type 2 receptor (H2R) signaling in mice. This study aimed to precisely elucidate the downstream effects of H2R activation in innate immune cells. Methods: Analyses using online databases of single-cell RNA sequencing of intestinal epithelial cells in mice and RNA sequencing of mouse immune cells were performed to determine the relative abundances of 4 histamine receptors among different cell types. Mouse neutrophils, which expressed greater amounts of H2R, were collected from the peritoneum of wild-type and H2R-deficient mice, of which low-density and high-density neutrophils were extracted by centrifugation and were subjected to RNA sequencing. The effects of H2R activation on neutrophil differentiation and its functions in colitis and inflammation-associated colon tumors were investigated in a mouse model of dextran sulfate sodium–induced colitis. Results: Data analysis of RNA sequencing and quantitative reverse-transcription polymerase chain reaction showed that Hrh2 is highly expressed in neutrophils, but barely detectable in intestinal epithelial cells. In mice, the absence of H2R activation promoted infiltration of neutrophils into both sites of inflammation and colonic tumors. H2R-deficient high-density neutrophils yielded proinflammatory features via nuclear factor-κB and mitogen-activated protein kinase signaling pathways, and suppressed T-cell proliferation. On the other hand, low-density neutrophils, which totally lack H2R activation, showed an immature phenotype compared with wild-type low-density neutrophils, with enhanced MYC pathway signaling and reduced expression of the maturation marker Toll-like receptor 4. Conclusions: Blocking H2R signaling enhanced proinflammatory responses of mature neutrophils and suppressed neutrophil maturation, leading to accelerated progression of inflammation-associated colonic tumorigenesis. |
| first_indexed | 2024-12-24T03:02:28Z |
| format | Article |
| id | doaj.art-dede34a6854d4efa898e633b9abcc4bd |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-12-24T03:02:28Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-dede34a6854d4efa898e633b9abcc4bd2022-12-21T17:18:10ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2022-01-01133717737Loss of H2R Signaling Disrupts Neutrophil Homeostasis and Promotes Inflammation-Associated Colonic Tumorigenesis in MiceSummaryZhongcheng Shi, PhD0Yuko Mori-Akiyama, MD1Wa Du, PhD2Robert Fultz, PhD3Yanling Zhao, PhD4Wenly Ruan, MD5Susan Venable6Melinda A. Engevik, PhD7James Versalovic, MD, PhD8Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas; Department of Pathology, Texas Children's Hospital, Houston, TexasDepartment of Pathology and Immunology, Baylor College of Medicine, Houston, Texas; Department of Pathology, Texas Children's Hospital, Houston, TexasDepartment of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OhioDepartment of Neuroscience, Cell Biology and Anatomy, University of Texas Medical Branch, Galveston, TexasDepartment of Pediatrics, Texas Children’s Cancer Center, Houston, TexasDepartment of Pediatrics, Baylor College of Medicine, Houston, Texas; Section of Gastroenterology, Hepatology, and Nutrition, Texas Children’s Hospital, Houston, TexasDepartment of Pathology and Immunology, Baylor College of Medicine, Houston, Texas; Department of Pathology, Texas Children's Hospital, Houston, TexasDepartment of Pathology and Immunology, Baylor College of Medicine, Houston, Texas; Department of Pathology, Texas Children's Hospital, Houston, TexasDepartment of Pathology and Immunology, Baylor College of Medicine, Houston, Texas; Department of Pediatrics, Baylor College of Medicine, Houston, Texas; Department of Pathology, Texas Children's Hospital, Houston, Texas; Correspondence Address correspondence to: James Versalovic, MD, PhD, Department of Pathology, Texas Children’s Hospital, 1102 Bates Avenue, Suite 830, Houston, Texas 77030. fax: (832) 825-1165.Background & Aims: We previously showed that histamine suppressed inflammation-associated colonic tumorigenesis through histamine type 2 receptor (H2R) signaling in mice. This study aimed to precisely elucidate the downstream effects of H2R activation in innate immune cells. Methods: Analyses using online databases of single-cell RNA sequencing of intestinal epithelial cells in mice and RNA sequencing of mouse immune cells were performed to determine the relative abundances of 4 histamine receptors among different cell types. Mouse neutrophils, which expressed greater amounts of H2R, were collected from the peritoneum of wild-type and H2R-deficient mice, of which low-density and high-density neutrophils were extracted by centrifugation and were subjected to RNA sequencing. The effects of H2R activation on neutrophil differentiation and its functions in colitis and inflammation-associated colon tumors were investigated in a mouse model of dextran sulfate sodium–induced colitis. Results: Data analysis of RNA sequencing and quantitative reverse-transcription polymerase chain reaction showed that Hrh2 is highly expressed in neutrophils, but barely detectable in intestinal epithelial cells. In mice, the absence of H2R activation promoted infiltration of neutrophils into both sites of inflammation and colonic tumors. H2R-deficient high-density neutrophils yielded proinflammatory features via nuclear factor-κB and mitogen-activated protein kinase signaling pathways, and suppressed T-cell proliferation. On the other hand, low-density neutrophils, which totally lack H2R activation, showed an immature phenotype compared with wild-type low-density neutrophils, with enhanced MYC pathway signaling and reduced expression of the maturation marker Toll-like receptor 4. Conclusions: Blocking H2R signaling enhanced proinflammatory responses of mature neutrophils and suppressed neutrophil maturation, leading to accelerated progression of inflammation-associated colonic tumorigenesis.http://www.sciencedirect.com/science/article/pii/S2352345X2100237XHistamineCimetidineInflammationColorectal Cancer |
| spellingShingle | Zhongcheng Shi, PhD Yuko Mori-Akiyama, MD Wa Du, PhD Robert Fultz, PhD Yanling Zhao, PhD Wenly Ruan, MD Susan Venable Melinda A. Engevik, PhD James Versalovic, MD, PhD Loss of H2R Signaling Disrupts Neutrophil Homeostasis and Promotes Inflammation-Associated Colonic Tumorigenesis in MiceSummary Cellular and Molecular Gastroenterology and Hepatology Histamine Cimetidine Inflammation Colorectal Cancer |
| title | Loss of H2R Signaling Disrupts Neutrophil Homeostasis and Promotes Inflammation-Associated Colonic Tumorigenesis in MiceSummary |
| title_full | Loss of H2R Signaling Disrupts Neutrophil Homeostasis and Promotes Inflammation-Associated Colonic Tumorigenesis in MiceSummary |
| title_fullStr | Loss of H2R Signaling Disrupts Neutrophil Homeostasis and Promotes Inflammation-Associated Colonic Tumorigenesis in MiceSummary |
| title_full_unstemmed | Loss of H2R Signaling Disrupts Neutrophil Homeostasis and Promotes Inflammation-Associated Colonic Tumorigenesis in MiceSummary |
| title_short | Loss of H2R Signaling Disrupts Neutrophil Homeostasis and Promotes Inflammation-Associated Colonic Tumorigenesis in MiceSummary |
| title_sort | loss of h2r signaling disrupts neutrophil homeostasis and promotes inflammation associated colonic tumorigenesis in micesummary |
| topic | Histamine Cimetidine Inflammation Colorectal Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X2100237X |
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