**1. Introduction**

The surface of the mouth is lined by the oral mucosa which was often considered to be more of a mechanic barrier than an active player involved in the modulation of the host response to various external stimuli in order to maintain mouth homeostasis.

The oral mucosa is permanently insulted by mechanic and chemical factors (like smoke, xenobiotics) as well as a plethora of microorganisms. Both the commensal and pathogen microorganisms, depending on their structure, represent triggers for the immune surveillance players hosted by the oral mucosa which have been intensively studied in the last years. Local defence in the oral cavity is provided by a complex network of cells with their receptors and molecules through which they respond to various ligands (microbial antigens, tissue degradation products,

nucleic acids). The interactions between gingival resident cells and oral microbiome are characteristic of clinical gingival health and homeostasis as well as for gingival inflammation. Host defence takes place in successive, sometimes overlapping stages. The innate immune response represents a homeostatic system which is the first line defence and defines the host inherited resistance to infection.

The immune system has a hierarchical organisation, all the immune and nonimmune cells involved being able to sense the pathogens through pattern recognition receptors (PRR) and then develop the immune response triggered by numerous proinflammatory mediators. PRRs detect and respond to conserved patterns originated in microorganisms and stress signals called pathogen- or damage-associated molecular patterns (PAMPS and DAMPS) [1].

Among PRRs, Toll-like receptors (TLRs) are the most intensively studied. In the oral mucosa TLRs are expressed in cells of the immune system including neutrophils, monocytes, macrophages, and not less important, dendritic cells, keratinocytes and endothelial cells [2]. TLR activation induces the local synthesis of cytokines and chemokines through different pathways. Part of these molecules are involved in the development of highly specific adaptive immunity ensured by T and B lymphocytes. Due to this ability, TLRs are considered to be the missing link between innate and acquired immunity.

Manipulating the oral immune response by development of drugs that inhibit adverse host reactions and promote beneficial effects might be of therapeutic or prophylactic importance in periodontal diseases.

This review intends to assess the importance of Toll-like receptors as main effectors of the innate immune response in the triggering, maintenance and progression of periodontal inflammation as well as of the involvement of synthetic molecules targeting TLR signalling networks in treating periodontal diseases.

#### **2. Methodology**

This chapter has been designed in order to assess the role of innate immune receptors, especially Toll-like receptors, as main effectors of the innate immune response triggered by various pathogens hosted in the subgingival film which are able to onset periodontal inflammation, as well as the involvement of synthetic molecules targeting TLR signalling pathways in treating periodontal diseases. Information processed has been sourced from the existing scientific literature and supplemented with our personal findings from experimental studies regarding TLR involvement in mediating innate immune response at oral mucosa level. We searched MEDLINE, Web of Science, SCOPUS, without language restriction, following terms "innate immunity" AND "periodontal inflammation" OR "periodontal disease" AND "TLR" OR "TLR therapeutic targets". Identification of specific literature also included manual search and screening of the citations of the relevant studies. The included studies were selected after reviewing the abstract and full-text for eligibility.

#### **3. Oral mucosa cells and the innate immune response**

The oral mucosa consists of a stratified oral epithelium formed by keratinocytes lining the inner connective tissue or *lamina propria* which has as main cells the fibroblasts and also proinflammatory cells originated in the bone marrow.

Three distinct phenotypes of oral mucosa are noted: lining, masticatory and specialised mucosa. The lining mucosa cover almost the entire mouth, excepting the rigid structures, such as the alveolar processes and the hard palate, which are covered by the masticatory mucosa, and the dorsal part of the tongue coated by the

#### *Innate Immune Response as a New Challenge in Periodontal Inflammation DOI: http://dx.doi.org/10.5772/intechopen.96801*

specialised mucosa [3]. The crevicular (CE) and junctional epithelium (JE) are the keystones for the antimicrobial barrier function of the oral mucosa. Compared to other types of epithelial cells, JE possesses fewer intercellular junctions, just desmosomes, and more intercellular spaces filled with gingival crevicular fluid (CF). Due to this histophysiology, JE allows the passage of CF, the carrier of inflammatory cells and soluble mediators, from the gingival connective tissue to the crevicular space. The changes of the dental biofilm and the metabolic products of bacteria trigger the synthesis of cytokines and increase the number of polymorphonuclear cells (PMNs) migrating to the initial site of inflammation. This early event, gingivitis, is followed by the appearance of other inflammatory cells (macrophages, lymphocytes, mononuclear and dendritic cells) and the persistence of inflammation of the teeth supporting tissues with progressive attachment loss and bone destruction, namely periodontitis [4]. The proinflammatory cells of the oral mucosa connective tissue are myeloid-originated immune cells such as monocytes, macrophages and dendritic cells which act as the first line of defence during infection, recognising, engulfing and killing bacteria, fungi or viruses. Recent data emphasises that it is not only the immune cells but also the fibroblasts and the keratinocytes that contribute to local immunity through the activation and modulation of specific immune receptors [5]. Fibroblasts activation triggered by the immune cells is involved in the remodelling of the extracellular matrix (ECM); moreover, under the stimulation of the endothelial cells derived signals, fibroblasts are able to differentiate into myofibroblasts important for wound healing of the masticatory mucosa [6]. Knowledge of how immune mechanisms and responses are controlled is essential for understanding the pathogenesis of periodontal inflammation. Bacteria are the most common pathogens in the case of gingivitis, followed by periodontitis, but both pathologies can also be caused by other pathogens like fungi, viruses or by metabolic imbalances. Until recently, innate and specific/adaptive immune responses had been arbitrarily proposed by immunologists as two distinct stages of the immunologic events. Later it was clarified that adaptive or acquired immune response evolved around innate immunity instead of replacing it. The development of acquired immunity is regulated through the activation of some myeloid and antigen presenting cells (APCs). Innate immunity should be considered as an immune system skill developed in order "to buy time" [7] until the acquired, more efficient host immune response, is primed. The immune system has a hierarchical organisation containing immune cells (monocytes, macrophages, neutrophils, dendritic cells (DCs), natural killer cells (NK), mast cells, eosinophils, basophils and newly identified innate lymphoid cells (ILCs), mucosal associated invariant T cells, ɣδT cells) and humoral circulating components (complement proteins, cytokines and chemokines secreted by those cells, along with various antimicrobial peptides, AMPs) [2, 8–11]. All the cells already mentioned are able to sense the pathogens through PRRs and then develop the innate immune response [12]. A limited number of PRRs are able to recognise a large number of pathogens. PRRs detect and respond to conserved motifs originated in microorganisms and stress signals called PAMPS and DAMPS [1]. PAMPs are evolutionarily conserved structures shared among pathogens, but not present in eukaryotes, which confer specificity to the innate immune response. These include lipopolysaccharides, peptidoglycans, bacterial lipoproteins, DNA and double stranded RNA [7]. DAMPs are endogenous ligands derived from host cells (tumour cells, dying cells) or products released from cells in response to various signals which produce inflammation in the absence of infection. DAMPs are often created in environments of trauma, ischemia, or tissue damage involved in various diseases (cancer, autoimmune disease, and atherosclerosis) and do not require pathogens infection [1, 13]. Inside the more generic term microbialassociated molecular patterns (MAMPs), one could consider commensal-associated

molecular patterns (CAMPs), as many microorganisms colonise the human body without causing disease [14]. PAMPs, MAMPs and DAMPs bind to PPRs which include mainly Toll-like receptors (TLRs), transmembrane C-type lectin-like receptors (CLRs), cytoplasmic NOD-like receptors (NLRs) and intracellular retinoic acid-inducible gene-I-like receptors (RLR) [13, 15]. PRR-ligand binding and their concomitant conformational changes prompt a cascade of downstream signalling that results in transcriptional and post-translational changes. Among these PRRs, TLRs have been studied most extensively.
