Elsevier

Translational Oncology

Volume 6, Issue 5, October 2013, Pages 596-606, IN8
Translational Oncology

Colon Macrophages Polarized by Commensal Bacteria Cause Colitis and Cancer through the Bystander Effect1,2

https://doi.org/10.1593/tlo.13412Get rights and content
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open access

Abstract

Intestinal commensal bacteria have recently been shown to trigger macrophages to produce diffusible clastogens (or chromosome-breaking factors) through a bystander effect (BSE) that mediates DNA damage and induces chromosomal instability in neighboring cells. Colon macrophages appear central to colon carcinogenesis and BSE through the expression of tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2). The former induces netrin-1, a regulator of intestinal epithelial cell apoptosis, and the latter generates trans-4-hydroxy-2-nonenal (4-HNE), an endogenous mutagen. To test whether colon macrophages are key effectors for BSE, we depleted these cells in interleukin-10 knockout mice colonized with Enterococcus faecalis using encapsulated liposomal clodronate (ELC), a bisphosphonate that causes macrophage apoptosis. We observed that E. faecalis polarizes colon macrophages to an M1 phenotype. In addition, depleting these cells suppressed COX-2 and TNF-α, blocked the formation of 4-HNE protein adducts, and inhibited up-regulation of netrin-1—all markers for BSE. Finally, treatment with ELC prevented colitis, β-catenin activation, and cancer formation. These results show that selected human commensals can polarize colon macrophages to the M1 phenotype and, when activated, serve as the key effector for bacterial-induced BSE. Our findings suggest that depleting M1-polarized macro-phages is a mechanism for the chemopreventive activity of bisphosphonates and that it represents a new strategy for preventing colon cancer induced by intestinal commensals.

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1

This study was supported by the Oklahoma Center for the Advancement of Science and Technology (HR10-032; X.W.), grant CA127893 (M.M.H.), and funds from the Francis M. Duffy Endowment. The authors disclose no conflicts.

2

This article refers to supplementary materials, which are designated by Figures W1 and W2 and are available online at www.transonc.com.