**7. Therapeutic perspectives of TLR targeting in periodontal inflammation**

Usual practical approaches to reduce bacterial levels to proportions manageable by the host innate immune system and limit the aggression of oral pathogens on periodontal tissues (scaling, root planning and meticulous oral hygiene techniques) [95] are often inefficient and for this reason adjunctive therapeutic strategies have been proposed in order to modulate host response.

Since their discovery, TLRs have emerged as pivotal mediators of innate host immune and inflammatory response. Due to their role in the recognition of PAMPS and DAMPS of various origins and the triggering of a proinflammatory response, TLR-signalling is regarded as a novel therapeutic target. That is why research was conducted to develop drugs that exploit TLRs signalling in immune therapy, drugs which are already tried to treat diseases, such as asthma and chronic obstructive pulmonary disease [96], AIDS [97], hepatitis B [98, 99], cancer [100, 101].

To date, several directions for targeting TLR-signalling pathways are discussed:


Despite the potential of TLRs to activate the synthesis of protective molecules against infection, they can also induce serious immunopathological reactions in case of overstimulation or insufficient control due to the limited action of some negative regulators. An increased number of negative regulators able to dampen the degree and duration of TLR-mediated inflammatory host response were proposed.

**Negative regulation** of TLR signalling can be exerted extracellularly (inhibition of receptor function) or intracellularly (inhibition of downstream signalling).

Negative regulation occurs through different mechanisms:


Negative regulators fail to control TLRs signalling because requiring a combination of effects, their loss leads to hyperactivation and pathogens develop strategies to evade TLR signalling [104]. TLRs may be novel therapeutic targets in periodontitis since manipulation of their signalling pathways contribute to the control of infection and inflammation and TLR agonists could be tested as vaccine adjuvants in treating periodontal inflammation [105].

**Vaccine adjuvants** exert their action by increasing antigen delivery to APCs, activating them to produce cytokines and by triggering T lymphocytes response [102, 106]. TLRs can function as adjuvant receptors for the recognition of certain antigens produced by microorganisms, the stimulation and maturation of APCs and the alerting of the immune system [24].

TLR agonists, similar but less toxic than PAMPS, are able to cause DCs maturation [102]. They are small molecules that mimic natural TLR ligands and could have improved pharmacological effects.

TLRs agonists are already clinically tested as vaccine adjuvants for cancer, allergic and infectious diseases [107].

#### **8. Conclusion**

Innate immune receptors are critical in maintaining periodontal health as well as in the progression of gingival inflammation by acting on the commensal microbiome and as a link to the activation of adaptive immunity. Due to the fact that TLRs are important in preserving the periodontium state in healthy conditions and TLR-inflammation is responsible for the destructive host reactions in periodontal diseases, the development of drugs that target TLR signalling and promote beneficial local effects would be of great success in such diseases.
