Indoleamine 2,3-dioxygenase expression regulates the survival and proliferation of Fusobacterium nucleatum in THP-1-derived macrophages

Ying Xue,Han Xiao,Songhe Guo,Banglao Xu,Yuehua Liao,Yixian Wu,Ge Zhang

doi:10.1038/s41419-018-0389-0

Abstract

Fusobacterium nucleatum (Fn) is a tumor-associated obligate anaerobic bacterium, which has a role in the progression of colorectal cancer (CRC). Fn can invade and promote colon epithelial cells proliferation. However, how Fn survives and proliferates in its host cells remains largely unknown. In this study, we aimed to determine the molecular mechanisms underlying the morphology, survival, and proliferation of Fn in THP-1-derived macrophages (dTHP1). For the first time, we found that Fn is a facultative intracellular bacterium that can survive and limited proliferate in dTHP1 cells up to 72 h, and a live Fn infection can inhibit apoptosis of dTHP1 cells by activating the PI3K and ERK pathways. Both Fn bacteria and dTHP1 cells exhibit obvious morphological changes during infection. In addition, Infection of Fn-induced indoleamine 2,3-dioxygenase (IDO) expression by TNF-α-dependent and LPS-dependent pathway in a time-dependent and dose-dependent manner, and the IDO-induced low tryptophan and high kynurenine environment inhibited the intracellular multiplication of Fn in dTHP1 cells. IDO expression further impaired the function of peripheral blood lymphocytes, permitting the escape of Fn-infected macrophages from cell death. IDO inhibition abrogated this effect caused by Fn and relieved immune suppression. In conclusion, we identified IDO as an important player mediating intracellular Fn proliferation in macrophages, and inhibition of IDO may aggravate infection in Fn-associated tumor immunotherapy.

Highlights

Some aggressive intracellular bacteria can survive and multiply in the cytoplasm of infected macrophages[1]
Maximal increases in the p-AKT and p-ERK levels occurred after 2–4 h (Fig. 2e, f). These results indicated that treated with live/heat-killed Fusobacterium nucleatum (Fn) exerted differentiation-like morphological changes, but not significant cytotoxicity on dTHP1 cells, and that macrophage apoptosis was inhibited during infection by activated PI3K/Akt and ERK signaling pathways
What’s more, Fn exhibits limited proliferation when it is cocultured with host cells under aerobic conditions, which demonstrates that the intracellular environment is more suitable than the extracellular environment for the survival of Fn in an un-strict anaerobic environment

Summary

Introduction

Some aggressive intracellular bacteria can survive and multiply in the cytoplasm of infected macrophages[1]. These facultative intracellular bacteria are shielded from humoral antibodies and can only be eliminated by a cellular immune response[2]. The treatment of intracellular bacteria is an ongoing clinical problem. Fusobacterium nucleatum (F. nucleatum, Fn) is an opportunistic commensal obligate anaerobic Gram-negative bacterium that is indigenous to the human oral cavity and has a role in periodontal disease. Accumulated evidence has demonstrated that Fn is associated with the development and carcinogenesis, and promote metastasis in colorectal cancer (CRC)[4,5,6]. Fn can Official journal of the Cell Death Differentiation Association

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