Role of inflammasomes in the pathogenesis of periodontal disease and therapeutics

Abstract

Inflammasomes are a group of multimolecular intracellular complexes assembled around several innate immune proteins. Recognition of a diverse range of microbial, stress and damage signals by inflammasomes results in direct activation of caspase‐1, which subsequently induces the only known form of secretion of active interleukin‐1β and interleukin‐18. Although the importance of interleukin‐1β in the periodontium is not questioned, the impact of inflammasomes in periodontal disease and its potential for therapeutics in periodontology is still in its very early stages. Increasing evidence in preclinical models and human data strongly implicate the involvement of inflammasomes in a number of inflammatory, autoinflammatory and autoimmune disorders. Here we review: (a) the currently known inflammasome functions, (b) clinical/preclinical data supporting inflammasome involvement in the context of periodontal and comorbid diseases and (c) potential therapies targeting inflammasomes. To clarify further the inflammasome involvement in periodontitis, we present analyses of data from a large clinical study (n = 5809) that measured the gingival crevicular fluid‐interleukin‐1β and grouped the participants based on current periodontal disease classifications. We review data on 4910 European‐Americans that correlate 16 polymorphisms in the interleukin‐1B region with high gingival crevicular fluid‐interleukin‐1β levels. We show that inflammasome components are increased in diseased periodontal tissues and that the caspase‐1 inhibitor, VX‐765, inhibits ~50% of alveolar bone loss in experimental periodontitis. The literature review further supports that although patients clinically present with the same phenotype, the disease that develops probably has different underlying biological pathways. The current data indicate that inflammasomes have a role in periodontal disease pathogenesis. Understanding the contribution of different inflammasomes to disease development and distinct patient susceptibility will probably translate into improved, personalized therapies.

Inflammasomes as contributors to periodontal disease

“…Both have DNA-binding domains and are pattern-recognition receptors that function as the sensor component of protein complexes called inflammasomes. [12][13][14] Inflammasomes are an essential component of the two-step process by which functional proinflammatory IL-1β is produced. In response to activation of cell surface receptors, genes encoding the IL-1β precursor and components forming the inflammasome are induced (named cell priming or signal 1).…”

“…In addition, gingival tissues show increased expression of proinflammatory Il1b. 12,20 To block inflammasome formation, our group administered the oral caspase-1 inhibitor VX-765 to mice with ligatureinduced periodontitis. The results showed that inhibition of caspase-1 led to an ≈50% reduction in alveolar bone loss, further supporting a major role of inflammasome formation in inflammatory-driven bone loss (Fig.…”

“…12 Targeting of IL-1β has been explored as a therapy for several diseases, which creates an opportunity for repurposing such drugs to treat other inflammatory diseases. 12 Blocking IL-1β production with VX-765 as an orally administered drug has been previously tested in clinical trials for epilepsy 21 and psoriasis (clinical trial: NCT00205465). Preclinical studies indicate that it may also be useful in Alzheimer disease 22 and some forms of arthritis.…”

AFF4 regulates osteogenic differentiation of human dental follicle cells

“…As a chronic infectious disease, periodontal disease is characterized by the inflammation of supporting tissues, such as gingiva, the periodontal membrane, the cementum and alveolar bone, resulting in loose or lost teeth. 2 Dental prosthetic treatment plays a vital role in achieving mechanical and partial functional restoration. However, the ultimate goal of treatment is regenerating the damaged periodontal tissue to restore the original composition and function.…”

O papel da interleucina-1beta na fisiopatogenia da doença periodontal: uma revisão de literatura

“…Embora as doenças periodontais inflamatórias resultem primariamente, de uma resposta imune à presença de bactérias do biofilme dental, a efetividade dessa resposta varia entre indivíduos e demonstra importância na determinação da susceptibilidade da doença uma vez que fatores microbiológicos podem ser agravados pela má higiene bucal e hábitos nocivos à saúde como o tabagismo e fatores sistêmicos como o diabetes, HIV, desordens imunológicas, estresse e gravidez podem interferir na condição periodontal e vice-versa (Gowen et al, 1983;Giannopoulou et al, 2003;de Queiroz et al, 2008;Marchesan et al, 2020).…”