Abstract
The NLRP3 inflammasome is overexpressed in gingiva of periodontitis patients but its role remains unclear. In our study, we use a periodontitis mouse model of ligature, impregnated or not with Porphyromonas gingivalis, in WT or NLRP3 KO mice. After 28 days of induction, ligature alone provoked exacerbated periodontal destruction in KO mice, compared to WT mice, with an increase in activated osteoclasts. No difference was observed at 14 days, suggesting that NLRP3 is involved in regulatory pathways that limit periodontitis. In contrast, in the presence of P. gingivalis, this protective effect of NLRP3 was not observed. Overexpression of NLRP3 in connective tissue of WT mice increased the local production of mature IL−1β, together with a dramatic mobilization of neutrophils, bipartitely distributed between the site of periodontitis induction and the alveolar bone crest. P. gingivalis enhanced the targeting of NLRP3-positive neutrophils to the alveolar bone crest, suggesting a role for this subpopulation in bone loss. Conversely, in NLRP3 KO mice, mature IL-1β expression was lower and almost no neutrophils were mobilized. Our study sheds new light on the role of NLRP3 in periodontitis by highlighting the ambiguous role of neutrophils, and P. gingivalis which affects NLRP3 functions.
Highlights
The activation of nucleotide‐binding leucine‐rich repeat protein 3 (NLRP3) inflammasome in inflammation-induced alveolar bone loss has emerged as an important mechanism in the pathogenesis of periodontitis [1, 2]
In NLRP3 knock out (KO) mice, the bone resorption continues to progress between day 14 to day 28 (+26.6%, compared to D14) suggesting that NLRP3 could play a role in the regulatory mechanisms that limit trauma-induced periodontal lesion
As Polymorphonuclear Neutrophils (PMN) are thought to be the most efficient phagocyte to destroy bacteria during periodontal infection [28], we examined whether their presence in the connective tissue neighboring the site of periodontitis induction will depend on NLRP3 or on the presence of exogenous P. gingivalis (Figure 7)
Summary
The activation of nucleotide‐binding leucine‐rich repeat protein 3 (NLRP3) inflammasome in inflammation-induced alveolar bone loss has emerged as an important mechanism in the pathogenesis of periodontitis [1, 2]. This multiprotein signaling platform assembles after the activation of membrane or cytosolic receptors by pathogens or endogenic cell stress [3, 4]. NLRP3 recruits an adaptor protein ASC which in turn binds to pro-caspase 1, allowing its cleavage in mature caspase-1 and its activation [3, 4]. This active tripartite complex ensures the maturation of pro-inflammatory cytokines from the IL-1. The presence of some inflammasome-related proteins in the saliva (NLRP3, ASC, and IL-1b) have recently been proposed as suitable biomarkers of the disease and may indicate cell death by pyroptosis [10]
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