Fusobacterium necrophorum Promotes Apoptosis and Inflammatory Cytokine Production Through the Activation of NF-κB and Death Receptor Signaling Pathways

Abstract

Fusobacterium necrophorum can cause liver abscess, foot rot in ruminants, and Lemire syndrome in humans, Also, its virulence factors can induce the apoptosis of macrophages and neutrophils. However, the detailed mechanism has not been fully clarified. This study investigated the mechanisms of apoptosis and inflammatory factor production in F. necrophorum–induced neutrophils and macrophages (RAW246.7). After infection of macrophages with F. necrophorum, 5-ethynyl-2’-deoxyuridine labeling assays indicated that F. necrophorum inhibited macrophage proliferation in a time- and dose-dependent manner. Hoechst staining and DNA ladder assays showed significant condensation of the nucleus and fragmentation of genomic DNA in F. necrophorum–infected macrophages, Annexin V (FITC) and propidium iodide (PI) assay confirmed the emergence of apoptosis in the macrophages and sheep neutrophils with F. necrophorum compared with the control. The group with significant apoptosis was subjected to RNA sequencing (RNA-Seq), and the sequencing results revealed 2581 up– and 2907 downregulated genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis of the differentially expressed genes showed that F. necrophorum drove apoptosis and production of inflammatory factors by activating genes related to the Nuclear Factor-κB (NF-κB) and death receptor pathways. Meanwhile, quantitative reverse transcription PCR and Western blot validation results were consistent with the results of transcriptome sequencing analysis. In conclusion, F. necrophorum induced apoptosis and production of pro-inflammatory factors through the NF-κB and death receptor signaling pathway, providing a theoretical basis for further mechanistic studies on the prevention and control of F. necrophorum disease treatment.

Fusobacterium nucleatum promotes inflammatory and anti-apoptotic responses in colorectal cancer cells via ADP-heptose release and ALPK1/TIFA axis activation

“…Previous studies have established that F. nucleatum is a potent activator of the pro-inflammatory transcription factor NF-κB in a wide range of cell-lines. 34 , 43 Exposure to F. nucleatum leads to the activation of TLRs, NODs, and ALPK1, resulting in NF-κB responses in various cell types; however, the impact of the molecules released in the microenvironment by the bacterium has not been characterized. 34 , 44–46 We used culture supernatants from F. nucleatum subsp.…”

Retropharyngeal abscess due to Fusobacterium necrophorum complicated by progressive internal carotid artery stenosis and multiple cranial nerve palsies

“…2 Fusobacterium necrophorum attaches to mammalian vascular endothelium mediated by the outer membrane protein, 3 subsequently activating immune cells through the NF-κB and death receptor signaling pathways. 4,5 The release of cytokines and reactive oxygen intermediates from these immune cells provokes inflammation and might trigger tissue damage. 5 Therefore, we considered that Fusobacterium necrophorum, directly invaded and attached to the arterial wall, inducing vascular endothelial damage, leading to gradual arterial stenosis/occlusion.…”

“…The etiology of gradual ICA stenosis/occlusion might be explained by endothelial damage to the arterial wall due to inflammation induced by Fusobacterium necrophorum 2 . Fusobacterium necrophorum attaches to mammalian vascular endothelium mediated by the outer membrane protein, 3 subsequently activating immune cells through the NF‐κB and death receptor signaling pathways 4,5 . The release of cytokines and reactive oxygen intermediates from these immune cells provokes inflammation and might trigger tissue damage 5 .…”