Key Elements of Gingival Epithelial Homeostasis upon Bacterial Interaction

Abstract

Epithelia are structurally integral elements in the fabric of oral mucosa with significant functional roles. Similarly, the gingival epithelium performs uniquely critical tasks in responding to a variety of external stimuli and dangers through the regulation of specific built-in molecular mechanisms in a context-dependent fashion at cellular levels. Gingival epithelial cells form an anatomic architecture that confers defense, robustness, and adaptation toward external aggressions, most critically to colonizing microorganisms, among other functions. Accordingly, recent studies unraveled previously uncharacterized response mechanisms in gingival epithelial cells that are constructed to rapidly exert biocidal effects against invader pathobiotic bacteria, such as Porphyromonas gingivalis, through small danger molecule signaling. The host-adapted bacteria, however, have developed adroit strategies to 1) exploit the epithelia as privileged growth niches and 2) chronically target cellular bactericidal and homeostatic metabolic pathways for successful bacterial persistence. As the overgrowth of colonizing microorganisms in the gingival mucosa can shift from homeostasis to dysbiosis or a diseased state, it is crucial to understand how the innate modulatory molecules are intricately involved in antibacterial pathways and how they shape susceptibility versus resistance in the epithelium toward pathogens. Thus, in this review, we highlight recent discoveries in gingival epithelial cell research in the context of bacterial colonizers. The current knowledge outlined here demonstrates the ability of epithelial cells to possess highly organized defense machineries, which can jointly regulate host-derived danger molecule signaling and integrate specific global responses against opportunistic bacteria to combat microbial incursion and maintain host homeostatic balance. These novel examples collectively suggest that the oral epithelia are equipped with a dynamically robust and interconnected defense system encompassing sensors and various effector molecules that arrange and achieve a fine-tuned and advanced response to diverse bacteria.

Keywords: chronic infection; danger signaling; epithelial defense mechanisms; epithelial homeostasis; gingival epithelia; opportunistic bacteria.

Figure.

Disrupted homeostatic environment in gingival epithelial cells upon invasion by opportunistic bacteria may lead to bacterial dysbiosis in tissues. In gingival epithelial cells, various host defense machineries are in place to combat potential bacterial offenses. (A) At the physiologic level, a minimal amount of ATP is released to the extracellular space via the pannexin 1 (Panx-1) hemichannel without activating P2X₇-mediated purinergic signaling and ROS-generating NADPH oxidase 2 (NOX2), resulting in a basal level of apoptosis. The equilibrium in extracellular purine concentration between ATP and adenosine is well balanced. Other danger signal molecules (e.g., HMGB1) and ubiquitination markers/cytosolic sensors of danger (including NDP52 and p62) remain mostly inactive. Antiapoptotic protein HSP27 is largely unphosphorylated. (B) Upon pathogenic bacterial insults, the extracellular ATP (eATP) release drastically increases, which then activates the P2X₇ receptor and NOX2 as antibacterial responses. HMGB1, which requires high eATP levels as a second stimulus, becomes translocated from the nucleus to the cytosol and extracellular space. However, opportunistic bacteria such as Porphyromonas gingivalis can modulate multiple antibacterial host machineries (NOX2, P2X₇, HMGB1, and ubiquitination marking) and stimulate probacterial host machineries (probacterial autophagy, CD73 activation, HSP27 phosphorylation, and A2a receptor signaling) for successful long-term colonization. (C) Opportunistic pathogens can invade host epithelial tissue and establish chronic colonization while penetrating deeper into the lamina propria. Uncontrolled growth of such pathogenic bacteria and further host tissue invasion lead to bacterial dysbiosis in the epithelia, ultimately initiating the formation of chronic inflammation and diseased epithelial tissues with increased formation of microvasculature.