Loss of H2R Signaling Disrupts Neutrophil Homeostasis and Promotes Inflammation-Associated Colonic Tumorigenesis in MiceSummary
| Autor: | Melinda A. Engevik, Robert Fultz, Susan Venable, Wenly Ruan, Yuko Mori-Akiyama, Yanling Zhao, James Versalovic, Zhongcheng Shi, Wa Du |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Carcinogenesis
Neutrophils RC799-869 HDN high-density neutrophil chemistry.chemical_compound Histamine receptor Mice Neutrophil differentiation HDGF hepatoma-derived growth factor Homeostasis TBS-T Tris Buffered Saline with Tween 20 Intestinal Mucosa Original Research TNF tumor necrosis factor Gastroenterology ERK extracellular signal-regulated kinase Diseases of the digestive system. Gastroenterology LDN low-density neutrophil Cell biology H2R KO histamine type 2 receptor deficient CXCR C-X-C Motif Chemokine Receptor CRC colorectal cancer LPS lipopolysaccharide Signal transduction medicine.symptom Cimetidine Histamine TLR Toll-like receptor PCNA proliferating cell nuclear antigen PBS phosphate-buffered saline Inflammation Proinflammatory cytokine ROS reactive oxygen species HSC hematopoietic stem cell MDSC myeloid-derived suppressor cell DSS dextran sulfate sodium medicine Animals Neutrophil homeostasis Colorectal Cancer Innate immune system Hepatology HR histamine receptor WT wild-type qRT-PCR quantitative reverse-transcription polymerase chain reaction IL interleukin PD-L1 programmed death-ligand 1 UC ulcerative colitis chemistry SM squamous metaplasia MAPK mitogen-activated protein kinase fMLP N-formylmethionyl-leucyl-phenylalanine |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology, Vol 13, Iss 3, Pp 717-737 (2022) Cellular and Molecular Gastroenterology and Hepatology |
| Popis: | 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. Graphical abstract |
| Databáze: | OpenAIRE |
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