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Histamine deficiency promotes inflammation-associated carcinogenesis through reduced myeloid maturation and accumulation of CD11b+Ly6G+ immature myeloid cells

Abstract

Histidine decarboxylase (HDC), the unique enzyme responsible for histamine generation, is highly expressed in myeloid cells, but its function in these cells is poorly understood. Here we show that Hdc-knockout mice show a high rate of colon and skin carcinogenesis. Using Hdc-EGFP bacterial artificial chromosome (BAC) transgenic mice in which EGFP expression is controlled by the Hdc promoter, we show that Hdc is expressed primarily in CD11b+Ly6G+ immature myeloid cells (IMCs) that are recruited early on in chemical carcinogenesis. Transplant of Hdc-deficient bone marrow to wild-type recipients results in increased CD11b+Ly6G+ cell mobilization and reproduces the cancer susceptibility phenotype of Hdc-knockout mice. In addition, Hdc-deficient IMCs promote the growth of tumor allografts, whereas mouse CT26 colon cancer cells downregulate Hdc expression through promoter hypermethylation and inhibit myeloid cell maturation. Exogenous histamine induces the differentiation of IMCs and suppresses their ability to support the growth of tumor allografts. These data indicate key roles for Hdc and histamine in myeloid cell differentiation and CD11b+Ly6G+ IMCs in early cancer development.

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Figure 1: Histamine-deficient Hdc−/− mice are highly susceptible to colorectal and skin carcinogenesis.
Figure 2: CD11b+Ly6G+ IMCs are the predominant source of Hdc-EGFP expression in the bone marrow.
Figure 3: Hdc deficiency upregulates CD11b+Gr-1+ and CD11b+Ly6G+ IMCs.
Figure 4: EGFP+ IMCs are recruited to inflamed tissue and stroma of colon tumor.
Figure 5: Bone marrow derived IMCs from Hdc−/− mice accelerate tumor growth.
Figure 6: Migration of circulating CD11b+Gr-1+ IMCs is RAGE dependent, and suppression of Hdc occurs through a methylation-dependent mechanism.

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Acknowledgements

We would like to thank S.P. Tu, S.W. Wang, S. Takaishi and H. Tomita for their helpful contributions. We thank K.S. Betz for her help with animal procedures. We are grateful to A. Leiter (University of Massachusetts) for the PKD4-NICD-EGFP plasmid. RAGE-knockout mice were kindly provided by A.M. Schmidt (Columbia University). This work was funded by the US National Institutes of Health grants RO1 DK048077, RO1 DK52778 and U54 CA126513. S.A. was supported by a Canadian Institutes for Health Research Clinician Scientist Award and Alberta Heritage Foundation for Medical Research Clinical Fellowship.

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X.D.Y. was involved in the study design, completion of experiments, data analysis and interpretation and manuscript preparation. W.A. constructed the Hdc-EGFP transgenic mouse and helped with examination of Hdc-EGFP expression. S.A. helped with the data interpretation and contributed to the manuscript preparation and revision. G.B. provided human colon specimen collection and did pathology assessments. R.A.F. carried out the microarray data analysis. G.J. helped with the colon cancer experiments and data analysis. H.P. helped with the skin carcinogenesis experiments and data analysis. B.S. performed histological analysis of the brains of Hdc-EGFP mice. T.G.D. carried out intravital microscopy studies. A.F. constructed the Hdc-knockout mice and provided helpful suggestions for our study. T.C.W. designed the study and contributed to the data analysis and writing of the manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Timothy C Wang.

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Supplementary Text and Figures

Supplementary Figures 1–17, Supplementary Tables 1–4 and Supplementary Methods (PDF 2118 kb)

Supplementary Video 1

Circulating EGFP-expressing blood cells in the ears of Hdc-EGFP mice with TPA-induced skin inflammation. An acute inflammatory response was induced in the ears of Hdc-EGFP mice by the application of a single dose of TPA (8.5 nmol, 20 μl per mouse). The video records 10 seconds of EGFP-expressing blood cells in the vessels using intravital microscopy 6 h after TPA treatment. (MOV 2340 kb)

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Yang, X., Ai, W., Asfaha, S. et al. Histamine deficiency promotes inflammation-associated carcinogenesis through reduced myeloid maturation and accumulation of CD11b+Ly6G+ immature myeloid cells. Nat Med 17, 87–95 (2011). https://doi.org/10.1038/nm.2278

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