Knocking out matrix metalloproteinase 12 causes the accumulation of M2 macrophages in intestinal tumor microenvironment of mice
- 31 July 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cancer Immunology, Immunotherapy
- Vol. 69 (8), 1409-1421
- https://doi.org/10.1007/s00262-020-02538-3
Abstract
MMP12 is mainly secreted by macrophages, is involved in macrophage development, and decomposes the extracellular matrix. Herein, we investigated whether macrophages would change in the intestinal tumor microenvironment after MMP12 knockout. Apc(Min/+);MMP12(-/-)mice were obtained by crossbreeding Apc(Min/+) mice with MMP12 knockout mice (MMP12(-/-) mice). The data showed that the number and volume of intestinal tumors were significantly increased in Apc(Min/+);MMP12(-/-) mice compared with Apc(Min/+) mice. Additionally, the tumor biomarkers CA19-9, CEA, and beta-catenin appeared relatively early in intestinal tumors in Apc(Min/+);MMP12(-/-) mice. The results demonstrated that knocking out MMP12 accelerated the tumor growth and pathological process. On further investigation of its mechanism, the proportions of M2 macrophages in the spleen and among peritoneal macrophages were significantly up-regulated in Apc(Min/+);MMP12(-/-) mice. Expression of M2 macrophage-related genes was up-regulated in tumor and peritoneal macrophages. The M2-related cytokine levels of IL-4 and IL-13 were increased in the serum of Apc(Min/+);MMP12(-/-)mice. In vitro, bone marrow-derived M2 macrophages were obtained by treating bone marrow cells with IL-4 and IL-13, and these M2 macrophages secreted cytokines being changed. This finding reveals the crucial role of MMP12 in macrophage development and provides a new target for the control of macrophage polarization. Knocking out MMP12 causes intestinal M2 macrophage accumulation in tumor microenvironment, promoting the growth of intestinal tumors in Apc(Min/+) mice.Funding Information
- National Natural Science Foundation of China (81773118)
- National Outstanding Youth Science Fund Project of National Natural Science Foundation of China (31471290)
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