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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 β-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.

P-selectin glycoprotein ligand 1 (SELPLG/ PSGL-1 ) is an inflammatory molecule that is functionally related to immune cell differentiation and leukocyte mobilization. However, the role of PSGL-1 in tumor development remains unknown. Therefore, this study investigates the mechanistic role of PSGL-1 in the development of intestinal tumors in colorectal cancer. Apc Min/+ mice are highly susceptible to spontaneous intestinal adenoma formation, and were crossbred with PSGL1-null mice to generate compound transgenic mice with a Apc Min/+ ; PSGL-1 -/- genotype. The incidence and pathologic features of the intestinal tumors were compared between the Apc Min/+ mice and Apc Min/+ ; PSGL-1 -/- -deficient mice, and the macrophages are likely the major source of macrophage inflammatory protein-1 gamma (MIP-1γ). Studies PSGL-1 -deficient mice showed increased susceptibility to develop intestinal tumors and accelerated tumor growth. Mechanistically, increased production of the mouse chemokine ligand 9 (CCL9/MIP-1γ) was found in the PSGL-1 -deficient mice, and the macrophages are likely the major source of macrophage inflammatory protein-1 gamma (MIP-1γ). Studies in vitro demonstrated that macrophage-derived MIP-1γ promoted colorectal cancer tumor cell growth through activating NFκB signaling. Conversely, restoration of the PSGL-1 signaling via bone marrow transplantation reduced MIP-1γ production and attenuated the ability of Apc Min/+ ; PSGL-1 -/- mice to generate intestinal tumors. In human colorectal cancer clinical specimens, the presence of PSGL-1 -positive cells was associated with a favorable tumor-node-metastasis staging and decreased lymph node metastasis. Implications: PSGL-1 deficiency and inflammation render intestinal tissue more vulnerable to develop colorectal tumors through a MIP-1γ/NFκB signaling axis. Mol Cancer Res; 15(4); 467-77. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Myeloid-derived suppressor cells (MDSCs) are found frequently in patients and mice bearing tumors, which derived from immature myeloid cells. In healthy individuals, immature myeloid cells formed in the bone marrow differentiating to dendritic cells, macrophages and neutrophils. However, it is unclear whether some gene deficiency will lead to MDSCs accumulation in mice without bearing tumor. Here, we observed that MDSCs accumulated in the bone marrow of matrix metalloproteinase 12 knockout mice (MMP12 −/− mice) compared with wild type mice (MMP12 +/+ mice). And the number of CD4 + cells dramatically decreased, regulatory T cells was up-regulation and MDSCs function were determined. The results suggested that immune surveillance have been impaired in MMP12 −/− transgenic mice. After intravenous administration of B16 murine melanoma cells, MMP12 −/− mice developed more metastatic pulmonary nodules than MMP12 +/+ mice. Meanwhile, more MDSCs appeared in the tumors of MMP12 −/− mice compared with those of MMP12 +/+ mice. Mechanistically, we performed a MDSC blocking assay, finding that blockade of MDSCs resulted in reducing growth of tumors in MMP12 −/− mice. Furthermore, we ascertained that macrophages in MMP12 −/− mice abundantly secrete IL-1β in bone marrow which induce the accumulation of MDSCs in the bone marrow. Together, these results demonstrated that the macrophages in MMP12 −/− mice could crosstalk with myeloid cells through IL-1β, inducing MDSCs accumulation, then contributing to tumor growth. It has revealed that the critical roles of macrophage in myeloid cells differentiation. [ABSTRACT FROM AUTHOR]

Objective Serum amyloid P conpoent (SAP), a member of the pentraxin family, interact with pathogens and cell debris to promote their removal by macrophages and neutrophils and is co-localized with atherosclerotic plaques in patients. However, the exact mechanism of SAP in atherogenesis is still unclear. We investigated whether SAP influence macrophage recruitment and foam cell formation and ultimately affect atherosclerotic progression. Methods we generated apoE −/− ; SAP −/− (DKO) mice and fed them western diet for 4 and 8 weeks to characterize atherosclerosis development. Results SAP deficiency effectively reduced plaque size both in the aorta (p = 0.0006 for 4 wks; p = 0.0001 for 8 wks) and the aortic root (p = 0.0061 for 4 wks; p = 0.0079 for 8wks) compared with apoE −/− mice. Meanwhile, SAP deficiency inhibited oxLDL-induced foam cell formation (p = 0.0004) compared with apoE −/− mice and SAP treatment increases oxLDL-induced foam cell formation (p = 0.002) in RAW cells. Besides, SAP deficiency reduced macrophages recruitment (p = 0.035) in vivo and in vitro (p = 0.026). Furthermore, SAP treatment enhanced CD36 (p = 0.007) and FcγRI (p = 0.031) expression induced by oxLDL through upregulating JNK and p38 MAPK phosphorylation whereas specific JNK1/2 inhibitor reduced CD36 (p = 0.0005) and FcγRI (P = 0.0007) expression in RAW cell. SAP deficiency also significantly decreased the expression of M1 and M2 macrophage markers and inflammatory cytokines in oxLDL-induced macrophages. Conclusion SAP deficiency mitigated foam cell formation and atherosclerotic development in apoE −/− mice, due to reduction in macrophages recruitment, polarization and pro-inflammatory cytokines and inhibition the CD36/FcγR-dependent signaling pathway. [ABSTRACT FROM AUTHOR]