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A Possible Therapeutic Approach for Periodontal Disease (Review) WORLD ACADEMY OF SCIENCES JOURNAL 3: 50, 2021 Targeting inflammasomes: A possible therapeutic approach for periodontal disease (Review) ANJU RANA, ARUNDEEP KAUR, FARRUKH FARAZ and SHRUTI TANDON Department of Periodontics, Maulana Azad Institute of Dental Sciences, New Delhi 110002, India Received May 31, 2021; Accepted August 11, 2021 DOI: 10.3892/wasj.2021.121 Abstract. Inflammasomes are cytosolic multimeric protein 1. Introduction complexes that typically comprise a sensor, an adaptor and the zymogen, procaspase‑1. Inflammasomes are a central Periodontitis is a chronic multifactorial inflammatory disease hub for signaling and the regulation of innate immunity. An associated with dysbiotic plaque biofilms and is characterized inflammasome assembles in response to a diverse range of by the progressive destruction of the tooth supporting pathogen‑associated molecular patterns or danger‑associated apparatus (1). This tissue destruction is initiated by an excessive molecular patterns. Inflammasomes further induce the matu‑ inflammatory host response to periodontal pathogenic ration of interleukin (IL)‑1β and 18 through the proteolytic bacteria. The production of the key pro‑inflammatory cleavage of pro‑IL‑1β and pro‑IL‑18. A number of previous cytokine, interleukin (IL)‑1β, by various host‑immune cells studies have highlighted the importance of the appropriate such as macrophages, oral fibroblasts, oral epithelial cells and activation of the inflammasome in homeostasis and in the osteoblasts induces the production of inflammatory mediators, pathogenesis of periodontal disease. Inflammasomes function matrix metalloproteinases and osteoclasts in periodontal as a homeostatic checkpoint to regulate the extent of inflam‑ tissues, leading to the destruction of connective tissue and mation in health and disease. Thus, further research is required alveolar bone (2). to uncover the modulators and regulators of the inflammasome T h e r ole of I L ‑1, p a r t icu la rly I L ‑1β, i n t h e p a t hogen e si s of p e r i‑ assembly. The enhanced knowledge of various strategies which odontal diseases was initially documented by Jandinski et al (3) may be used to regulate an excessive inflammatory response at in 1991. They demonstrated that the number of cells stained the cellular and molecular level may lead to the development with anti‑human IL‑1β antibody was almost 3‑fold higher in of more effective strategies for the treatment and prevention of periodontally diseased tissue compared with normal tissue, periodontal disease, as well as its associated systemic diseases. suggesting that IL‑1β produced by cells in periodontal tissues was related to the pathological processes associated with peri‑ odontal disease. Kinane et al (4) measured the amount of IL‑1 Contents in gingival crevicular fluid during human experimental gingi‑ vitis; an increase in IL‑1 levels was observed with subsequent 1. Introduction gingival inflammation, suggestive of IL‑1, an early biomarker of 2. Background, role and function of inflammasomes gingival inflammation. In addition, it has been well‑established 3. Inflammasome activation that an increased IL‑1 production is a strong indicator of the 4. Inflammasomes in periodontal disease susceptibility to severe periodontitis and peri‑implantitis (5). 5. Therapeutics targeting the inflammasome This IL‑1β remains in an inactive form as pro‑IL‑1β. A series 6. Conclusion and future perspectives of processes results in the formation of a multiprotein complex termed the ‘inflammasome’ in the cytosol, which is responsible for converting pro‑IL‑1β into its activated form, IL‑1β (6). The inhibition of inflammasome activation by periodontal pathogens may allow other bacteria in the subgingival ecosystem to survive for longer period of time, thus contributing to persistent chronic inflammation and further periodontal damage (7). It has also been reported that titanium ions also stimulate inflammasome Correspondence to: Dr Anju Rana, Department of Periodontics, Maulana Azad Institute of Dental Sciences, B.S. Zafar Marg, activation, which may be responsible for inflammation around New Delhi 110002, India implants in peri‑implantitis (8). Current evolving evidence E‑mail: [email protected] suggests that the inflammasome plays an essential role in the pathogenesis and progression of periodontal and peri‑implant Key words: inflammasomes, periodontal diseases, periodontitis, disease. Thus, the main objective of the present review was to NLRP3, periodontal inflammation provide a short overview of the inflammasome and to discuss various strategies that may target inflammasomes that may be used as novel approaches for periodontal treatment. 2 RANA et al: TARGETING INFLAMMASOMES: FUTURE PERSPECTIVES 2. Background, role and function of inflammasomes differentiation of T‑cells occurs once mature IL‑1β and IL‑18 are recognized by their receptors. Moreover, inflammasome Inflammation is a double‑edged sword. Inadequate inflamma‑ activation induces pyroptosis in host immune cells. Pyroptosis tion leads to persistent pathogenic infection whereas excessive occurs through the cleavage of caspase‑1, leading to the inflammation leads to the development of chronic inflamma‑ oligomerization of the N‑terminal gasdermin D fragment of tory diseases. Therefore, it is essential for the host to balance gasdermin D protein (cytoplasmic protein) and insertion into the extent of inflammation by proper inflammasome activation. the plasma cell membrane, resulting in pore formation. This As regards the characterization of the inflammasome, pore formation by gasdermin D induces cell lysis and the according to Martinon et al (9), the inflammasome is defined release of intracellular components (DAMPS) into the extra‑ as ‘the set of intracellular protein complexes that enable cellular environment, accentuating inflammation. autocatalytic activation of inflammatory caspases, which drives host immune responses by releasing mature cytokines 3. Inflammasome activation and alarmins into circulation and by inducing pyroptosis’. The role of the inflammasome in the innate immunity was Inflammasome activation involves a two‑step signaling first documented by Martinon et al (9) in 2002, followed by process, i.e., cell priming along with cell recognition and Bostanci et al (10) in 2009, who reported its involvement in formation. Cell priming process serves two purposes: i) The the pathogenesis of periodontal disease. Since then, studies transcriptional and translational upregulation of inflam‑ focusing on the inflammasome in periodontal diseases have masome components (comprising of the sensor molecule, been published (7,10‑15). caspase‑1 and pro‑IL‑1β); and ii) the post‑translational altera‑ The cytosolic multimeric protein structures of inflam‑ tion of the sensor molecule and adaptor molecule (ASC). masomes mainly comprise of three components: i) a sensor The transcriptional upregulation of inflammasome compo‑ molecule; ii) an adaptor, and iii) a zymogen procaspase‑1. nents occurs through the activation of the transcription factor, The sensor molecule has a ‘nucleotide‑binding domain NF‑κB, caused by the recognition of various PAMPs or DAMPs leucine‑rich repeat‑containing receptor (NLR)’ and the adaptor that engage multiple Toll‑like receptors or by the cytokines, has ‘apoptosis‑associated speck‑like protein containing a TNF and IL‑1β. These host cell receptors and molecules are caspase‑recruitment domain (ASC)’ (16). recognized by bacterial components, which initiate different To date, >10 different inflammasomes have been reported in signaling pathways. The second step is recognizing a PAMP the literature, which include NLR family pyrin domain (PYD) or DAMP specific to each inflammasome, which then induces containing protein (NLRP)1, NLRP3, NLRP6, NLRP12, pyrin, inflammasome formation and activation (7). Once PAMPs or NLR family apoptosis inhibitory protein (NAIP)/NLR family DAMPs specific for certain sensor molecules, such as pattern caspase activation and recruitment domain (CARD) domain recognition receptors (PRRs) are recognized, the oligomeriza‑ containing (NLRC)4, retinoic acid inducible gene 1 (RIG‑1), tion of the PRR is induced. absent in melanoma‑2 (AIM2), interferon (IFN), gamma‑induc‑ ible protein 16 (IFI16), NLRC3 and NLP6 (15,17,18). NLRP1 4. Inflammasomes in periodontal disease is recognized as the first protein forming an inflammasome along with its potential role in the host innate immunity and Various in vitro, animal and clinical studies have demonstrated inflammatory diseases (7). A well‑documented inflammasome the role of inflammasomes (mainly NLRP3) in periodontal is NLRP3. NLRP3 also known as cryopyrin, is predominantly inflammation (10,11,21,22). Higher levels of inflammasome expressed in macrophages, and is encoded by the NLRP3 gene expression have been detected in the gingival and salivary on human chromosome 1 (19). samples of patients with periodontal disease (13,23). Mature Inflammasome triggering is associated with high levels of cytokines processed by caspase‑1, mainly IL‑1β, control osteo‑ inflammation; thus, it should be strictly regulated to prevent clastic differentiation and activity by exerting direct effects its aberrant activation. Under normal healthy conditions, on osteoclasts and indirectly by modulating the expression the host balances the extent of inflammation by the proper of receptor activator of nuclear factor‑κB ligand (RANKL) activation of inflammasomes. Inflammasomes function as in other immune cells. It has been demonstrated
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