Commensal microbiota maintains alveolar macrophages with a low level of CCL24 production to generate anti-metastatic tumor activity

Min Cheng,Shilian Hu,Zhigang Tian,Yongyan Chen,Tingjuan Xu,Wen Chen,Ling Yang,Gan Shen,Liang Wang,Guodong Shen

doi:10.1038/s41598-017-08264-8

Min Cheng, Shilian Hu + Show 8 more

Open Access

https://doi.org/10.1038/s41598-017-08264-8

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Abstract

Microbiota maintains host tissue homeostasis and influences tissue-resident macrophages. However, the mechanisms by which commensal bacteria in regulating the alveolar macrophages remain unclear. Here, by using an antibiotic-treated (Abt) mouse model, we found commensal bacteria depletion induced lower frequencies and numbers of alveolar macrophages. This effect was accompanied by the altered levels of genes involved in several biological pathways, including M2 macrophage polarization, as determined by gene expression analysis. Alveolar macrophages from the Abt mice had higher protein and gene levels of Arg1, CCL24, IL-13, IL-10, IL-6 and IL-1β, which could be recovered to normal levels by reconstructing commensal bacteria in the upper respiratory of Abt mice. Moreover, alveolar macrophages performed significant enhancement of M2 functions, especially CCL24 secretion, in the Abt mice challenged with B16/F10 melanoma. Adoptive transfer of normal alveolar macrophages or antibody neutralization of CCL24 significantly recovered the decrease of γδT17 cells and rescued the defect anti-tumor response of Abt mice, indicating the elevated amount of alveolar macrophage-derived CCL24 inhibited γδT cell mediated anti-tumor response. In conclusion, we demonstrated the ability of commensal bacteria to maintain alveolar macrophages with a low level of CCL24 production, which was necessary for the normal anti-tumor response in the lung.

Highlights

Enormous number of commensal microbiota reside on the surface of the body, including the skin, gastrointestinal, respiratory and urogenital tracts
After five weeks of antibiotics treatment, the frequency and number of macrophages were significantly lower in the lungs of the Abt mice than in the lungs of the controls (Fig. 1a and b), and these were confirmed by immunofluorescence analysis (Fig. 1c and d)
We firstly demonstrated that commensal microbiota maintained alveolar macrophages with a low level of CCL24 production to generate anti-metastatic tumor activity

Summary

Introduction

Enormous number of commensal microbiota reside on the surface of the body, including the skin, gastrointestinal, respiratory and urogenital tracts. The microbiota integrates into whole-organism physiology and maintains host tissue homeostasis Disruption of this homeostasis would induce various disorders, such as infections, autoimmunity and autoinflammation, metabolic syndromes and cancer[1]. In 2014, we reported that commensal microbiota can regulate the host immune surveillance of tumor cells in the lungs through γδT17 cell immunity[3]. As the mice grow after birth, commensal microbiota of the mucosal tissue is gradually established and improved, necessarily regulating the local immune microenvironment including the airway. The role of commensal bacteria in regulating the mucosal macrophages, such as those in the lungs, during the immune surveillance of tumor cells remains unclear. We used an antibiotic-treated (Abt) mouse model and firstly demonstrated that commensal microbiota maintained alveolar macrophages with a low level of CCL24 production, which was necessary for them to generate anti-tumor activity

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Conclusion