Oral Microbes and Mucosal Dendritic Cells, “Spark and Flame” of Local and Distant Inflammatory Diseases

Abstract

Mucosal health and disease is mediated by a complex interplay between the microbiota ("spark") and the inflammatory response ("flame"). Pathobionts, a specific class of microbes, exemplified by the oral microbe Porphyromonas gingivalis, live mostly "under the radar" in their human hosts, in a cooperative relationship with the indigenous microbiota. Dendritic cells (DCs), mucosal immune sentinels, often remain undisturbed by such microbes and do not alert adaptive immunity to danger. At a certain tipping point of inflammation, an "awakening" of pathobionts occurs, wherein their active growth and virulence are stimulated, leading to a dysbiosis. Pathobiont becomes pathogen, and commensal becomes accessory pathogen. The local inflammatory outcome is the Th17-mediated degenerative bone disease, periodontitis (PD). In systemic circulation of PD subjects, inflammatory DCs expand, carrying an oral microbiome and promoting Treg and Th17 responses. At distant peripheral sites, comorbid diseases including atherosclerosis, Alzheimer's disease, macular degeneration, chronic kidney disease, and others are reportedly induced. This review will review the immunobiology of DCs, examine the complex interplay of microbes and DCs in the pathogenesis of PD and its comorbid inflammatory diseases, and discuss the role of apoptosis and autophagy in this regard. Overall, the pathophysiological mechanisms of DC-mediated chronic inflammation and tissue destruction will be summarized.

The Ubiquitin System and A20: Implications in Health and Disease

“…However, the most potent antigen-presenting cell of the initial response is the dendritic cell (DC). In addition to detecting invading pathogens, they also capture, process, and present antigens to lymphocytes, subsequently controlling the differentiation and quality of T- and B-cell proliferation (Meghil and Cutler 2020). At this acute stage, the cumulative functions of innate cells are necessary to control microbial insult, resolve inflammation, and establish homeostasis with no damage to oral cavity tissues.…”

“…Specifically, A20 expression in CD11c + DCs was shown to attenuate the severity of the hypertensive response by limiting the activation of T cells in the kidney and draining lymph nodes (Lu et al 2019). In the oral mucosa, DCs play a critical role in immune defense by inducing antigen-specific T-cell activation, differentiation, and proliferation (Meghil and Cutler 2020). However, the role of A20 in regulating the function of DCs in the oral cavity has not been previously investigated but can certainly offer insights into the causal link between dendritic cell function and periodontal breakdown.…”

“…In fact, hepatocyte-specific A20 deficiency was shown to render mice more susceptible to spontaneous liver inflammation and enhanced apoptosis (Catrysse et al 2016). In the oral mucosa, the stringent regulation of immune cell life span and turnover is an important dimension of immune homeostasis, and a disruption of apoptosis can contribute to chronic inflammation seen in periodontitis (Meghil and Cutler 2020). In fact, insufficient A20 levels sensitize gingival keratinocytes to bacteria and TNF-induced apoptosis, supporting the notion that A20-targeted therapies can help maintain the integrity of the gingival epithelium and restore impaired periodontal tissue homeostasis (Li et al 2020).…”

“…A20 has also been shown to interact with autophagic proteins p62 and ATG16L1, regulating autophagic, inflammatory, and cell death responses (Kanayama et al 2015; Slowicka et al 2019). Autophagy is another critical intracellular pathway involved in the maintenance of oral tissue homeostasis and periodontium integrity (Meghil and Cutler 2020). In fact, A20 was shown to exert antiosteoclastogenic effects via the inhibition of TRAF6-dependent autophagy in human periodontal ligament cells under hypoxic conditions, which mimics the microenvironment frequently seen in periodontitis (Yan et al 2020).…”

Role of Dendritic Cells in Inflammation

“…Mucosal tissues are complex environments characterized by the constant interplay between microbiota and mucosal DCs. The review by Dr. Meghil highlights the cascade of events that may lead from oral loss of tolerance toward chronic inflammation and the onset of several diseases [ 3 ].…”