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Beyond Regulation of Acid Secretion: A Novel Role for Histamine in Gastric Macrophage Differentiation and Function

  • Diane Bimczok
    Correspondence
    Correspondence Address correspondence to: Diane Bimczok, DVM, PhD, Department of Microbiology and Cell Biology, Montana State University, 2155 Analysis Drive, Bozeman, Montana 59718.
    Affiliations
    Department of Microbiology and Cell Biology, Montana State University, Bozeman, Montana
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Open AccessPublished:November 03, 2022DOI:https://doi.org/10.1016/j.jcmgh.2022.10.007
      Histamine is a biogenic amine that is widely recognized as a mast cell–derived inflammatory mediator and that contributes to local inflammatory reactions by increasing vascular permeability. In the stomach, histamine also is a key driver of acid secretion by parietal cells, and histamine receptor antagonists, such as cimetidine or ranitidine, are commonly used as long-term treatments to inhibit parietal cell acid production in patients with acid reflux disease. Although mast cells are considered the major producers of histamine in the body, histamine secretion by multiple other cell types including neuronal cells and myeloid cells has been reported. In human gastric mucosa, enterochromaffin-like cells were found to be the major source of histamine for the regulation of parietal cell acid secretion.
      To elucidate the role of histamine in gastric physiology, several previous studies used a histamine-deficient mouse, the histidine decarboxylase knockout mouse (HDC-KO), which lacks the biosynthetic enzyme required to generate histamine from the amino acid L-histidine.
      • Ohtsu H.
      • et al.
      Mice lacking histidine decarboxylase exhibit abnormal mast cells.
      Over the course of multiple months, the HDC-KO mice develop spontaneous hypertrophic gastropathy with dysregulated gastric epithelial cell differentiation.
      • Nakamura E.
      • et al.
      Lack of histamine alters gastric mucosal morphology: comparison of histidine decarboxylase-deficient and mast cell-deficient mice.
      ,
      • Nozaki K.
      • et al.
      Altered gastric chief cell lineage differentiation in histamine-deficient mice.
      Similar pathologic changes to the gastric architecture are seen in a rare human disease, Ménétrier disease,
      • Huh W.J.
      • Coffey R.J.
      • Washington M.K.
      Menetrier's disease: its mimickers and pathogenesis.
      making this mouse model translationally relevant. Development of hypertrophic gastropathy in the HDC-KO model was thought to be caused by histamine regulating both parietal cell acid secretion and gastric epithelial cell growth and lineage differentiation.
      • Nozaki K.
      • et al.
      Altered gastric chief cell lineage differentiation in histamine-deficient mice.
      However, in an interesting new study published in this edition of Cellular and Molecular Gastroenterology and Hepatology, Kim et al
      • Kim K.
      • et al.
      Histamine signaling is essential for tissue macrophage differentiation and suppression of bacterial overgrowth in the stomach.
      demonstrate that vastly more complex pathways and feedback loops involving the bone marrow, peripheral immune mechanisms, the gastric microbiome, and gastric epithelial cells lead to hypertrophic gastropathy on histamine deficiency.
      Kim et al
      • Kim K.
      • et al.
      Histamine signaling is essential for tissue macrophage differentiation and suppression of bacterial overgrowth in the stomach.
      observed that, in addition to the morphologic and functional changes to the gastric epithelium, HDC-KO mice developed severe gastric bacterial overgrowth and inflammatory changes to the gastric mucosa with a significant long-term increase in gastric macrophages. Importantly, hyperplastic gastropathy did not occur in germ-free HDC-KO mice, indicating a central role for the gastric microbiota in the regulation of epithelial cell growth and differentiation. Based on these observations and previous studies that had shown a role for histamine in myeloid cell differentiation,
      • Yang X.D.
      • et al.
      Histamine deficiency promotes inflammation-associated carcinogenesis through reduced myeloid maturation and accumulation of CD11b+Ly6G+ immature myeloid cells.
      ,
      • Xu L.
      • et al.
      Histamine promotes the differentiation of macrophages from CD11b(+) myeloid cells and formation of foam cells through a Stat6-dependent pathway.
      the authors focused on the role of gastric macrophages in the development of hypertrophic gastropathy and bacterial dysbiosis in HDC-KO mice.
      First, single cell RNASeq analysis was used to perform an in-depth characterization of murine gastric macrophage population, which revealed 3 major macrophage subsets: (1) F4/80+ CD11b+ IL-1β+ M1 macrophages, (2) F4/80+CD11b+ CD93+ M2 macrophages, and (3) a F4/80neg CD11b+ MHC-II+ subset with high phagocytic capacity. In functional experiments, gastric macrophages from the HDC-KO mice showed significantly decreased phagocytosis, associated with a reduced expression of complement receptors (CD21/35). Kim et al
      • Kim K.
      • et al.
      Histamine signaling is essential for tissue macrophage differentiation and suppression of bacterial overgrowth in the stomach.
      then used a highly creative experimental approach to differentiate between the role of parietal cells versus macrophages in gastric dysbiosis. In the HDC-KO mice, all bacteria were eliminated using antibiotics, the stomach was acidified through drinking water, and then the HDC-KO mice were gavaged with bacteria from wild-type mice. Significant bacterial overgrowth was still present in the HDC-KO mice despite normal gastric pH, demonstrating that gastric dysbiosis in HDC-KO mice was not merely caused by reduced parietal cell acid secretion but involved a defective host response. Importantly, experiments using bone marrow chimeras demonstrated that transfer of wild-type macrophages into HDC-KO mice fully eliminated gastric inflammation and restored gastric morphology and bacterial colonization. These results confirm a role of gastric macrophages for hypertrophic gastropathy and gastric dysbiosis in HDC-KO mice and also point to the bone marrow rather than the stomach itself as a key site for histamine-dependent macrophage differentiation.
      It is important to define to what extent the phagocyte defects in the HDC-KO mice impact Helicobacter pylori pathogenesis, given previous contradictory reports on macrophage function in murine H pylori infection. Whereas Viladomiu et al
      • Viladomiu M.
      • et al.
      Cooperation of gastric mononuclear phagocytes with Helicobacter pylori during colonization.
      showed that gastric CD11b+F4/80hiCD64+CX3CR1+ macrophages suppress gastric inflammation but are unable to effectively control H pylori colonization, Schumacher et al
      • Schumacher M.A.
      • et al.
      Gastric Sonic Hedgehog acts as a macrophage chemoattractant during the immune response to Helicobacter pylori.
      showed that CD11b+F4/80+Ly6Chi macrophages contribute to gastric inflammation in H pylori–infected mice. Notably, a previous H pylori infection study found milder cytokine responses and reduced gastric pathology in HDC-KO mice compared with wild-type mice infected at 6 to 8 weeks of age.
      • Klausz G.
      • et al.
      Effects of Helicobacter pylori infection on gastric inflammation and local cytokine production in histamine-deficient (histidine decarboxylase knock-out) mice.
      However, most changes in the study by Kim et al
      • Kim K.
      • et al.
      Histamine signaling is essential for tissue macrophage differentiation and suppression of bacterial overgrowth in the stomach.
      required 12 months to develop. Future research also is needed to determine WHETHER hyperplastic gastropathy in human Ménétrier disease involves histamine deficiency, macrophage dysfunction, or gastric dysbiosis.

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