This LtxA-induced activation is mediated by interactions with the outer membrane receptors LFA-1 and P2X 7, which are highly expressed by THP-1 cells. In this research, we first confirmed that THP-1 cells are sensitive to LtxA and respond to LtxA exposure with pyroptosis. Here, we used the THP-1 human monocyte cell line, which can be stimulated to differentiate into macrophage- or osteoclast-like cells. It was previously reported that LtxA indirectly activates bone resorption by releasing substantial amounts of bioactive IL-1β. actinomycetemcomitans were shown to have a significantly increased risk of developing periodontal attachment loss. Adolescents colonized with highly leukotoxic A. actinomycetemcomitans LtxA that are associated with the enhanced bone-resorbing activity. In the present study, we investigated virulence mechanisms induced by A. In addition, LtxA stimulated differentiation towards osteoclasts-like cells in LPS-treated THP-1 cells. actinomycetemcomitans leukotoxicity mediates activation of the NLRP3 inflammasome and cell-to-cell communication in the induced pro-inflammatory cell death. However, pit formation was not significantly enhanced by LtxA. Here, LPS prevented LtxA-mediated cell death but failed to induce osteoclast differentiation on its own. THP-1 cells treated with lipopolysaccharide (LPS) and LtxA together differentiated into an osteoclast-like phenotype. The results showed that LtxA induced inflammatory cell death, which involved activation of the NLRP3 inflammasome and gap junction cell-to-cell communication. Cell-to-cell communication was assessed by fluorescent parachute assays, and THP-1 differentiation into osteoclast-like cells was investigated microscopically. The effect of LtxA on activation of the inflammasome complex was studied in THP-1 wild type and in NLRP3- and ASC knockout cells. The aim of the present study was to increase the understanding of LtxA-induced leukocyte activation mechanisms and of possible associated osteoclast differentiation. The leukotoxin (LtxA) expressed by this bacterium induces a rapid pro-inflammatory response in leukocytes that results in cell death. Carriers of highly leukotoxic genotypes of Aggregatibacter actinomycetemcomitans are at high risk for rapid degradation of tooth-supporting tissues.
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