title: Colon Macrophages Polarized by Commensal Bacteria Cause Colitis and Cancer through the Bystander Effect.
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.
authors.affiliation: The Muchmore Laboratories for Infectious Diseases Research, Research Service, Department of Veterans Affairs Medical Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK ; Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Yang
authors.forename: Xingmin
authors.initials: X
authors.lastname: Wang
authors.forename: Thomas
authors.initials: T
authors.lastname: Huycke
authors.forename: Danny R
authors.initials: DR
authors.lastname: Moore
authors.forename: Stanley A
authors.initials: SA
authors.lastname: Lightfoot
authors.forename: Mark M
authors.initials: MM
authors.lastname: Huycke