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

Abstract

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