Porphyromonas gingivalis promotes the transendothelial migration of monocytes through the MIF/p38/JAM-A axis in monocytes

Abstract

Abstract Although several previous studies have reported that periodontitis is associated with the progression of atherosclerosis, the underlying mechanisms remain unclear. Periodontal bacteria can cause atherosclerosis by promoting the attachment of monocytes to endothelial cells through the circulatory system. However, it has not been elucidated whether periodontal pathogens stimulate transendothelial migration (TEM) of monocytes and the mechanisms. In the present study, we investigated the effect of periodontal bacteria on the development of atherosclerosis by observing the contribution of periodontal pathogens on TEM. Porphyromonas gingivalis (P. gingivalis) promoted both the adhesion and TEM of THP-1 cells, whereas Fusobacterium nucleatum (F. nucleatum) only promoted adhesion. Interestingly, infection of monocytes with F. nucleatum induced aggregation, which may inhibit TEM of monocytes. Pathogen infection in THP-1 cells had significantly increased expression of pro-inflammatory cytokines. Pathogen infection increased the expression of adhesion-related molecules in both THP-1 and EA.hy926 cells. However, the expression of junctional adhesion molecule-A (JAM-A) increased in THP-1 cells but decreased in EA.hy926 cells following infection. Promotion of JAM-A expression by periodontal pathogens in THP-1 cells was found to be regulated by the macrophage migration inhibitory factor (MIF) signaling pathway. P38 signaling activated by P. gingivalis stimulation was reduced by neutralizing the MIF receptor CD74 antibody, but JNK and ERK1/2 pathways were not involved. Increased adhesion of monocytes to endothelial cells was also observed in mice intravenously injected with P. gingivalis. This study provides new insights into the mechanisms by which P. gingivalis promotes monocyte adhesion and TEM via the MIF–p38–JAM-A axis.