TY - JOUR
T1 - Loss of H2R Signaling Disrupts Neutrophil Homeostasis and Promotes Inflammation-Associated Colonic Tumorigenesis in Mice
AU - Shi, Zhongcheng
AU - Mori-Akiyama, Yuko
AU - Du, Wa
AU - Fultz, Robert
AU - Zhao, Yanling
AU - Ruan, Wenly
AU - Venable, Susan
AU - Engevik, Melinda A.
AU - Versalovic, James
N1 - Funding Information:
Funding This study was supported by National Institutes of Health T32 grant T32DK007664-28 (W.R. and M.A.E.) and grant U01CA170930 (J.V.), and the Digestive Diseases Center National Institutes of Health National Institutes of Health / National Institute of Diabetes and Digestive and Kidney Diseases grant P30 DK56338-06A2 (J.V.).
Funding Information:
Conflicts of interest This author discloses the following: James Versalovic has received unrestricted research support from BioGaia AB, and serves on the scientific advisory boards of Seed Health, Biomica, and Plexus Worldwide. The remaining authors disclose no conflicts.Funding This study was supported by National Institutes of Health T32 grant T32DK007664-28 (W.R. and M.A.E.) and grant U01CA170930 (J.V.), and the Digestive Diseases Center National Institutes of HealthNational Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases grant P30 DK56338-06A2 (J.V.).
Publisher Copyright:
© 2021 The Authors
PY - 2022/1
Y1 - 2022/1
N2 - 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.
AB - 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.
KW - Cimetidine
KW - Colorectal Cancer
KW - Histamine
KW - Inflammation
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U2 - 10.1016/j.jcmgh.2021.11.003
DO - 10.1016/j.jcmgh.2021.11.003
M3 - Article
C2 - 34781022
AN - SCOPUS:85123092219
SN - 2352-345X
VL - 13
SP - 717
EP - 737
JO - CMGH
JF - CMGH
IS - 3
ER -