Implication of Toll/IL-1 receptor domain containing adapters in Porphyromonas gingivalis-induced inflammation

Abstract

Periodontitis is induced by periodontal dysbiosis characterized by the predominance of anaerobic species. TLRs constitute the classical pathway for cell activation by infection. Interestingly, the Toll/IL-1 receptor homology domain adapters initiate signaling events, leading to the activation of the expression of the genes involved in the host immune response. The aim of this study was to evaluate the effects of Porphyromonas gingivalis on the expression and protein-protein interactions among five TIR adapters (MAL, MyD88, TRIF, TRAM and SARM) in gingival epithelial cells and endothelial cells. It was observed that P. gingivalis is able to modulate the signaling cascades activated through its recognition by TLR4/2 in gingival epithelial cells and endothelial cells. Indeed, MAL-MyD88 protein-protein interactions associated with TLR4 was the main pathway activated by P. gingivalis infection. When transient siRNA inhibition was performed, cell viability, inflammation, and cell death induced by infection decreased and such deleterious effects were almost absent when MAL or TRAM were targeted. This study emphasizes the role of such TIR adapter proteins in P. gingivalis elicited inflammation and the precise evaluation of TIR adapter protein interactions may pave the way for future therapeutics in both periodontitis and systemic disease with a P. gingivalis involvement, such as atherothrombosis.

Porphyromonas gingivalis regulates atherosclerosis through an immune pathway

“…However, it has also been shown that TLR4 plays a protective role in AS progression ( 201 ), but the actual role of TLR4 still needs to be elucidated in the highly variable and dynamic inflammatory environment induced by P. gingivalis . Deeper studies revealed that P. gingivalis -induced inflammatory responses almost disappeared when targeted to inhibit the adapter MAL or TRAM of the Toll/IL-1 receptor (TIR) domain on ECs ( 202 ). In terms of intracellular pathways, P. gingivalis inhibits ECs proliferation, and promotes endothelial-mesenchymal transitions and apoptosis in a TLR-NF-κB axis dependent manner, compromising endothelial integrity and leading to the loss of ECs’ ability to repair themselves ( 203 ).…”