Sterol Regulatory Element-Binding Protein-1c Regulates Inflammasome Activation in Gingival Fibroblasts Infected with High-Glucose-Treated Porphyromonas gingivalis

Abstract

Background: Porphyromonas gingivalis is a major bacterial species implicated in the progression of periodontal disease, which is recognized as a common complication of diabetes. The interleukin (IL)-1β, processed by the NLR family pyrin domain containing 3 (NLRP3) inflammasome, has been identified as a target for pathogenic infection of the inflammatory response. However, the effect of P. gingivalis in a high-glucose situation in the modulation of inflammasome activation in human gingival fibroblasts (HGFs) is not well-understood.Methods: P. gingivalis strain CCUG25226 was used to study the mechanisms underlying the regulation of HGF NLRP3 expression by the infection of high-glucose-treated P. gingivalis (HGPg).Results: HGF infection with HGPg increases the expression of IL-1β and NLRP3. We further demonstrated that the upregulation of sterol regulatory element-binding protein (SREBP)-1c by activation of the Akt and p70S6K pathways is critical for HGPg-induced NLRP3 expression. We showed that the inhibition of Janus kinase 2 (JAK2) blocks the Akt- and p70S6K-mediated SREBP-1c, NLRP3, and IL-1β expression. The effect of HGPg on HGF signaling and NLRP3 expression is mediated by β1 integrin. In addition, gingival tissues from diabetic patients with periodontal disease exhibited higher NLRP3 and SREBP-1c expression.Conclusions: Our findings identify the molecular pathways underlying HGPg-dependent NLRP3 inflammasome expression in HGFs, providing insight into the effect of P. gingivalis invasion in HGFs.

Candida albicans Shields the Periodontal Killer Porphyromonas gingivalis from Recognition by the Host Immune System and Supports the Bacterial Infection of Gingival Tissue

“…Interestingly, the reduction of CD14 expression was found in that same study to depend on the hemagglutinin/adhesion properties of gingipains and cause a hypo-responsiveness to bacterial challenge [65]. However, further studies are needed to clarify the mechanism of retaining of such changes by host cells [66,67].…”

Oral Biofilms from Symbiotic to Pathogenic Interactions and Associated Disease –Connection of Periodontitis and Rheumatic Arthritis by Peptidylarginine Deiminase

“…P. gingivalis can adhere to and invade human fibroblasts ( Pathirana et al, 2008 ; Irshad et al, 2012 ; Zhang et al, 2014 ), and such bacterial infection induces secretion of pro-inflammatory mediators, including IL-6 and IL-8, via TLR-dependent and -independent pathways ( Liu et al, 2014 ; Palm et al, 2015 ). In addition, P. gingivalis infection induces caspase-independent apoptosis as well as regulation of the inflammasome activation ( Desta and Graves, 2007 ; Kuo et al, 2016 ). Such diverse responses of the infected fibroblasts affect biological functions and differentiation of other cell types, implicating their regulatory role in progression of periodontitis and consequent chronic inflammation ( Zhang et al, 2014 ; Tzach-Nahman et al, 2017 ).…”

Cell Type–Specific Decomposition of Gingival Tissue Transcriptomes

“…SREBP1C is a key lipogenic transcription factor that regulates cholesterol and fatty acid metabolism and synthesis (Wang et al 2015). Activation and higher levels of SREBP1C have been reported in periodontal disease-affected tissue in patients with diabetes (Kuo et al 2016). Upregulation of SREBP1C was critical for induction of NLRP3, an inflammasome component, by high-glucose-treated P. gingivalis (Kuo et al 2016).…”