Table 5.

Manipulation of TLR-mediated immunity by P. gingivalis and possible counterstrategies

Mechanisms	Intervention	Refs.
1) Manipulation of TLR2 vs. TLR4 responses by  altering its lipid A structure	Blockade of hemin- binding proteins? *	(3, 40)
2) Upregulation of negative regulators of TLR  signalling(IRAK-M)	Inhibition of IRAK-M activity? **	(49)
3) Induction of TLR2 inside-out signalling in  macrophages for CR3-dependent inhibition of  IL-12	CR3 antagonists (e.g., XVA143)	(84, 235)
4) Degradation of essential TLR coreceptors  (CD14) or immunostimulatory cytokines	Gingipain inhibitors (e.g., KYT-1, KYT-36) or anti-gingipain vaccines	(11, 111, 213)
5) Instigation of CXCR4/TLR2 cross-talk for  suppressing macrophage-mediated clearance	CXCR4 antagonists (e.g. AMD3100)	(89)

^*The rationale is based on the finding that alteration of lipid A structure is regulated by microenvironmental hemin concentrations (3).

^**This could be achieved through specific RNA interference or microRNA-based approaches, although upregulation of undesirable inflammatory responses may be a serious side-effect.