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