**6. Nucleotide-binding oligomerisation domain (NOD)-like receptors signalling**

The NOD-like (NLR) family of innate intracellular receptors detects several PAMPs and endogenous molecules. In humans, this family contains ~20 members classified into five different subfamilies according to their structure: (i) NLRA which has an acidic transactivation domain, (ii) NLRB - with a baculovirus inhibitor of apoptosis protein repeat, (iii) NLRC – contains a CARD domain and includes NOD1 and NOD2, (iv) NLRP – which as a pyrin domain and responds to multiple stimuli forming a multiprotein complex termed NALP – inflammasome, and the last (v) NLRX, containing an uncharacterized domain [31, 77, 78]. A number of putative ligands of NLRs have been reported, but the field of NLRs ligand identification is still open. It is unclear whether NLRs, as well as TLRs, are able to interact directly through the LRR domain with their ligands [79]. NODs are cytosolic PRRs that bind to peptidoglycan from bacterial cell wall. NOD1 and NOD2 are present more or less in the same immune cells as TLR: NOD1 on human mononuclear cells, macrophages, epithelial cells, including those from oral epithelium, and dendritic cells, while NOD2 is present mostly on phagocytic cells: macrophages, DCs, neutrophils [80, 81] and Paneth cells of the small intestine [82–84]. NOD1 is involved in recognising cell wall compounds from Gram-negative bacteria, while NOD2 can sense both Gram-positive and Gram-negative bacterial cell wall components [82, 85]. NOD1 plays an essential role in innate immune response, its downstream signalling inducing the production of proinflammatory cytokines (IL-6, IL-8, TNF-α, hBD-2) and chemokines, as well as compounds with immunoregulatory and antimicrobial properties (IFN-γ, hBD-1).

The inflammasome comprises proteins that are assembled by intracytoplasmic PRRs. A multitude of inflammasomes exist and these can be activated through various mechanisms in order to secrete proinflammatory cytokines [86]. Once activated by PAMPs or DAMPs, the NLRPs undergo conformational changes that trigger the activation of caspase-1. Afterwards, the maturation of proinflammatory cytokines, such as IL-1β and IL-18, to their active forms follows and finally results in inflammation and pyroptosis, a cellular event confirmed in periodontal inflammation [87, 88]. Pyroptosis is a proinflammatory programmed cell death pathway uniquely dependent on caspase-1 [89]. The mechanism and outcome of pyroptosis are different from those of apoptosis which actively inhibits inflammation.

Fourteen members of the NLRP subfamily are described [90]. Among these, expression NLRP2 inflammasome was reported to be decreased in gingival epithelia infected by *P. gingivalis* [91]. NLRP1 and NLRP3 are proposed to be involved in inflammasome function in addition to the cytoplasmic receptor absent in melanoma 2 (AIM2) [92]. AIM2 is the first non-NLR family member that was identified to mediate inflammasome assembly and activate the caspase-1 pathway [93] having mainly cytosolic dsDNA from viruses, bacteria or the host as ligands. NLRP1, NLRP3 and AIM2 may exhibit inflammasome activity in diseases such as type 2 diabetes, essential hypertension or rheumatoid arthritis [88].

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

It is confirmed that the expression level of the inflammasome changes as the inflammation destroys the gingival tissues [91, 94]. In an immunohistochemical study, Xue et al. described a dissimilar expression pattern of NLRP1, NLRP3 and AIM2 in chronic and aggressive periodontitis, demonstrating their involvement in the pathogenesis of periodontal diseases to different degrees [88]. NLRP3 was significantly higher in chronic periodontitis and more expressed in the gingival epithelium than in *lamina propria* both in periodontitis and gingivitis. The intensity was gradually weaker from the top to the basal membrane in chronic periodontitis and opposite in aggressive periodontitis, which strengthens the idea that the bacteria outside the gingiva are more important in the pathogenesis of gingivitis when in aggressive periodontitis the host factor may be more importantly involved [88]. NLRP1 seems not to be an important biomarker for distinguishing gingivitis, aggressive and chronic periodontitis, because they observed that NLRP1 was barely expressed in gingival tissues in both conditions.
