A systems biological study on heterogeneous Porphyromonas gingivalis lipopolysaccharides: human gingivalfibroblasts interaction : molecular mechanisms and implications inperiodontal pathogenesis

Porphyromonas gingivalis is a keystone periodontopathogen and its lipopolysacharide (LPS) is strongly associated with periodontal disease. A long-standing controversy occurs on the role of P. gingivalis LPS in induction of innate host response in different cell types. It has recently been found that P. gingivalis LPS displays remarkable heterogeneity with both tetra- (LPS1435/1449) and penta-acylated (LPS1690) lipid A structures. However, the potential effects of heterogeneous structures of P. gingivalis LPS on modulating host innate responses in human gingival fibrobalsts (HGFs) - the most abundant cells in gingiva remain unclear. To fulfill this research gap, a comprehensive study on the P. gingivalis LPS-HGFs interations was undertaken. The effects of P. gingivalis LPS1435/1449 and LPS1690 on the expression profiles of pro-inflammatory cytokines were investigated (Chapter III). P. gingivalis LPS1690 (not LPS1435/1449) significantly upregulated the expression of IL-6, IL-8 and TNF-α, suggesting that P. gingivalis LPS may differentially modulate the expression of pro-inflammatory cytokines. The effects of P. gingivalis LPS on the expression of MMPs 1-3 and TIMP-1, and regulation of MMP-3 were then determined (Chapter IV). P. gingivalis LPS1690 markedly induced MMP-3 expression through p38 MAPK and ERK signal pathways, whereas TIMP-1 was greatly upregulated by P. gingivalis LPS1435/1449. These findings suggest that P. gingivalis LPS heterogeneity may differentially modulate the expression and regulation of MMP-3. Based on these findings, the involvements of TLR2/4 and the downstream signaling pathways were explored (Chapter V). P. gingivalis LPS1690 induced TLR4 expression, whereas TLR2 was upregulated by P. gingivalis LPS1435/1449. NF-κB pathway played a dominant role in P. gingivalis LPS1690-induced expression of IL-6 and IL-8. These findings suggest that the two isoforms of P. gingivalis LPS critically interact with TLR2 and TLR4, and may determine the subsequent activation of signal transduction cascades that differentially modulate immuno-inflammatory response. P. gingivalis could thereby evade innate host defense and contribute to periodontal pathogenesis. To obtain a holistic profile of heterogeneous P. gingivalis LPS-HGFs interactions, a systems biology-based study through proteomics, metabolomics and bioinformatics approaches was undertaken (Chapter VI). Pro-inflammatory proteins (e.g. Cyclophilin, Annexins, IL-6 and Cathepsins) were induced by P. gingivalis LPS1690. In contrast, anti-inflammatory proteins (e.g. ANXA1, ANXA2 and Gal-1) were upregulated by P. gingivalis LPS1435/1449. P. gingivalis LPS1690 also induced antioxidant defense molecules like MnSOD and PRDXs. Secretomic analysis showed that immuno-inflammatory mediators, extra-cellular proteases and matrix proteins were differentially modulated by the two isoforms of P. gingivalis LPS as well. These findings demonstrate that host responses such as immuno-inflammatory activity, oxidative stress and anti-oxidant defense may be differentially modulated and regulated by the heterogeneous P. gingivalis LPS. Further study shows that P. gingivalis LPS1435/1449 and LPS1690 differentially modulate oxidative stress response and antioxidant expression, and differential regulation of MnSOD could be a critical determinant of periodontal homeostasis (Chapter VII). The present findings may bring new insight into the molecular mechanisms of periodontal pathogenesis. Targeting the mechanisms of shift in lipid A structures of P. gingivalis LPS may be a potential strategy to develop novel approaches to control and prevent periodontal diseases.

並列關鍵字

Porphyromonas gingivalis. ； Endotoxins. ； Fibroblasts.

國際替代計量

主題瀏覽