Periodontitis is a chronic inflammatory disease that destroys tooth-supporting tissues in a wide range of populations (Ra et al., 2020). It has a poor prognosis and is the main cause of tooth loss in several patients (Eke et al., 2020). At present, immune homeostasis disorders, which have been attributed to oral microbial dysbiosis, are considered responsible for periodontitis pathogenesis in hosts (Xu et al., 2020). According to a previous theory related to periodontitis, cell pattern recognition receptors (PRRs) recognize lipopolysaccharide (LPS), a key virulence factor, and induce an inflammatory response, leading to the recruitment of immune cells in periodontal tissue, destruction of collagen fibers, and irreversible bone loss (Lunar Silva & Cascales, 2021). In addition to surgical treatment and basic maintenance therapy, regulating the immune recognition activity of PRRs to control the inflammation level and promote tissue repair has become a trending research direction (Song et al., 2017).

PRRs are cell perception proteins that sense potentially “non-self” molecules in the extracellular matrix and initiate appropriate defenses to avoid cellular damage induced by invading microbes (Gong et al., 2020). This is a major process adapted by the body manage microbial infection and promote the repair of damaged tissue (Kuo et al., 2018). This physiological process is important for appropriate functioning of the innate immune system. PPRs can be categorized as classical PRRs, (e.g., Toll-like receptors (TLRs) and NOD-like receptors (NLRs)) (Takeuchi & Akira, 2010) and non-canonical PRRs (e.g., caspase-11) (Kayagaki et al., 2011). TLR4 is the most classical LPS recognition pathway, and LPS recognition by TLR4 depends on myeloid differentiation factor 2 (MD2) (Cochet & Peri, 2017). However, an assessment of associated risk factors revealed that TLR4 is not the only factor influencing periodontal disease(Ozturk & Vieira, 2009). These results suggest that other immune recognition receptors may regulate the occurrence and development of inflammation in periodontitis. Kayagaki et al. (Kayagaki et al., 2011) reported the biological function of caspase-11 as a PRR in bacteria-mediated inflammation. Researchers have gained a new understanding of many infectious inflammatory diseases based on the ability of caspase-11 to recognize LPS independent of any framework. This ability has made caspase-11 substantially different from classical PRRs, especially TLRs and NLRs, in the immune recognition process.

TLR-mediated immune recognition plays an absolute role in periodontal disease when immune cells are exposed to bacterial infection (Kantrong et al., 2019). Oka et al. (2021) suggested that caspase-4, generally considered a mouse caspase-11 counterpart in human cells (Cheng et al., 2021), is downstream of TLR4 in inflammatory responses. However, caspase-11 could independently recognize LPS and cleave pro-IL-1β to release activated IL-1β in the bacteria-induced inflammatory response (Gabarin et al., 2021). In addition, Ding et al. (2020) demonstrated that NLRP3 activation is associated with caspase-4 activation in human periodontitis, further supporting the hypothesis that caspase-11/4 is a potential Porphylinomonas gingivalis (P. gingivalis) LPS receptor. Unfortunately, no study has investigated the role of caspase-11 in experimental periodontitis models.

The study investigated the effect of caspase-11/4 in periodontitis using gingival samples from clinical periodontitis and established a rat periodontitis model. The role of caspase-11 in P. gingivalis LPS recognition was investigated through siRNA transfection in vitro. Thus, revealing the possible mechanism of caspase-11 may provide a theoretical basis for periodontitis treatment and further drug development.