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.
1
Over the course of multiple months, the HDC-KO mice develop spontaneous hypertrophic gastropathy with dysregulated gastric epithelial cell differentiation.2
,3
Similar pathologic changes to the gastric architecture are seen in a rare human disease, Ménétrier disease,4
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.3
However, in an interesting new study published in this edition of Cellular and Molecular Gastroenterology and Hepatology, Kim et al5
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
5
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,6
,7
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
5
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
8
showed that gastric CD11b+F4/80hiCD64+CX3CR1+ macrophages suppress gastric inflammation but are unable to effectively control H pylori colonization, Schumacher et al9
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.10
However, most changes in the study by Kim et al5
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.References
- Mice lacking histidine decarboxylase exhibit abnormal mast cells.FEBS Lett. 2001; 502: 53-56
- Lack of histamine alters gastric mucosal morphology: comparison of histidine decarboxylase-deficient and mast cell-deficient mice.Am J Physiol Gastrointest Liver Physiol. 2004; 287: G1053-G1061
- Altered gastric chief cell lineage differentiation in histamine-deficient mice.Am J Physiol Gastrointest Liver Physiol. 2009; 296: G1211-G1220
- Menetrier's disease: its mimickers and pathogenesis.J Pathol Transl Med. 2016; 50: 10-16
- Histamine signaling is essential for tissue macrophage differentiation and suppression of bacterial overgrowth in the stomach.Cell Mol Gastroenterol Hepatol. 2022; XX (XXX–XXX)
- Histamine deficiency promotes inflammation-associated carcinogenesis through reduced myeloid maturation and accumulation of CD11b+Ly6G+ immature myeloid cells.Nat Med. 2011; 17: 87-95
- Histamine promotes the differentiation of macrophages from CD11b(+) myeloid cells and formation of foam cells through a Stat6-dependent pathway.Atherosclerosis. 2017; 263: 42-52
- Cooperation of gastric mononuclear phagocytes with Helicobacter pylori during colonization.J Immunol. 2017; 198: 3195-3204
- Gastric Sonic Hedgehog acts as a macrophage chemoattractant during the immune response to Helicobacter pylori.Gastroenterology. 2012; 142: 1150-1159
- Effects of Helicobacter pylori infection on gastric inflammation and local cytokine production in histamine-deficient (histidine decarboxylase knock-out) mice.Immunol Lett. 2004; 94: 223-228
Article Info
Publication History
Published online: November 03, 2022
Accepted:
October 11,
2022
Received:
September 26,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
Conflicts of interest The authors disclose no conflicts.
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- Histamine Signaling Is Essential for Tissue Macrophage Differentiation and Suppression of Bacterial Overgrowth in the StomachCellular and Molecular Gastroenterology and HepatologyVol. 15Issue 1
- PreviewHistamine in the stomach traditionally is considered to regulate acid secretion but also has been reported to participate in macrophage differentiation, which plays an important role in tissue homeostasis. Therefore, this study aimed to uncover the precise role of histamine in mediating macrophage differentiation and in maintaining stomach homeostasis.
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