Porphyromonas gingivalisImpairs Oral Epithelial Barrier through Targeting GRHL2

Abstract

Oral mucosa provides the first line of defense against a diverse array of environmental and microbial irritants by forming the barrier of epithelial cells interconnected by multiprotein tight junctions (TJ), adherens junctions, desmosomes, and gap junction complexes. Grainyhead-like 2 (GRHL2), an epithelial-specific transcription factor, may play a role in the formation of the mucosal epithelial barrier, as it regulates the expression of the junction proteins. The current study investigated the role of GRHL2 in the Porphyromonas gingivalis ( Pg)–induced impairment of epithelial barrier functions. Exposure of human oral keratinocytes (HOK-16B and OKF6 cells) to Pg or Pg-derived lipopolysaccharides ( Pg LPSs) led to rapid loss of endogenous GRHL2 and the junction proteins (e.g., zonula occludens, E-cadherin, claudins, and occludin). GRHL2 directly regulated the expression levels of the junction proteins and the epithelial permeability for small molecules (e.g., dextrans and Pg bacteria). To explore the functional role of GRHL2 in oral mucosal barrier, we used a Grhl2 conditional knockout (KO) mouse model, which allows for epithelial tissue-specific Grhl2 KO in an inducible manner. Grhl2 KO impaired the expression of the junction proteins at the junctional epithelium and increased the alveolar bone loss in the ligature-induced periodontitis model. Fluorescence in situ hybridization revealed increased epithelial penetration of oral bacteria in Grhl2 KO mice compared with the wild-type mice. Also, blood loadings of oral bacteria (e.g., Bacteroides, Bacillus, Firmicutes, β- proteobacteria, and Spirochetes) were significantly elevated in Grhl2 KO mice compared to the wild-type littermates. These data indicate that Pg bacteria may enhance paracellular penetration through oral mucosa in part by targeting the expression of GRHL2 in the oral epithelial cells, which then impairs the epithelial barrier by inhibition of junction protein expression, resulting in increased alveolar tissue destruction and systemic bacteremia.

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“…For example, Porphyromonas gingivalis (P. gingivalis) lipopolysaccharide induces the overproduction of CC chemokine ligand 2 (CCL2) via toll-like receptor-4 (TLR-4)/NF-κB signaling in OLP, which may sustain or exacerbate the chronic inflammation of OLP. 64 Fungal disorders are related to the aggravation of OLP. 62 Candida was detected in 37% of patients, 65 while Aspergillus was Fig.…”

The Association between Periodontitis and Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis

“…Periodontitis is a chronic oral in ammatory condition caused by an exaggerated inflammatory response against polymicrobial colonization in the dental plaque. Porphyromonas gingivalis is the bacteria commonly responsible for bio lm formation around the gingival area [7]. A recent National Health and Nutrition Examination Survey (NHANES) found that almost 10% of Americans su ered from severe periodontitis [8].…”

Gastrin-Releasing Peptide (GRP) Stimulates Osteoclastogenesis in Periodontitis

“…Gingival ECs are the first line of host defense as they function as a physical barrier against invading pathogens. Recent studies have demonstrated that P. gingivalis can invade ECs to activate resident periodontal tissue cells which, in turn, affects cell proliferation, differentiation, and migration of precursor immune cells into the wound environment [ 30 , 31 ]. These responses lead to the production of various inflammatory and immune mediators that contribute to the destruction of tissue components including bone [ 30 ].…”