AUTHOR=Hu Lijun , Liu Yan , Kong Xuehua , Wu Rui , Peng Qi , Zhang Yan , Zhou Lan , Duan Liang 

TITLE=Fusobacterium nucleatum Facilitates M2 Macrophage Polarization and Colorectal Carcinoma Progression by Activating TLR4/NF-κB/S100A9 Cascade

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.658681

DOI=10.3389/fimmu.2021.658681

ISSN=1664-3224

ABSTRACT=<p><italic>Fusobacterium nucleatum</italic> (<italic>Fn</italic>) has been considered as a significant contributor in promoting colorectal carcinoma (CRC) development by suppressing host anti-tumor immunity. Recent studies demonstrated that the aggregation of M2 macrophage (M<italic>φ</italic>) was involved in CRC progress driven by <italic>Fn</italic> infection. However, the underlying molecular mechanisms are poorly characterized. Here, we investigated the role of <italic>Fn</italic> in M<italic>φ</italic> polarization as well as its effect on CRC malignancy. <italic>Fn</italic> infection facilitated differentiation of M<italic>φ</italic> into the M2-like M<italic>φ</italic> phenotype by <italic>in vitro</italic> study. Histological observation from <italic>Fn</italic>-positive CRC tissues confirmed the abundance of tumor-infiltrating M2-like M<italic>φ</italic>. <italic>Fn</italic>-induced M2-like M<italic>φ</italic> polarization was weakened once inhibiting a highly expressed damage-associated molecular pattern (DAMP) molecule S100A9 mainly derived from <italic>Fn</italic>-challenged M<italic>φ</italic> and CRC cells. In addition, <italic>Fn</italic>-challenged M2-like M<italic>φ</italic> conferred CRC cells a more malignant phenotype, showing stronger proliferation and migration characteristics <italic>in vitro</italic> and significantly enhanced tumor growth <italic>in vivo</italic>, all of which were partially inhibited when S100A9 was lost. Mechanistic studies further demonstrated that activation of TLR4/NF-<italic>κ</italic>B signaling pathway mediated <italic>Fn</italic>-induced S100A9 expression and subsequent M2-like M<italic>φ</italic> activation. Collectively, these findings indicate that elevated S100A9 in <italic>Fn</italic>-infected CRC microenvironment participates in M2-like M<italic>φ</italic> polarization, thereby facilitating CRC malignancy. Furthermore, targeting TLR4/NF-<italic>κ</italic>B/S100A9 cascade may serve as promising immunotherapeutic strategy for <italic>Fn</italic>-associated CRC.</p>