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.

Keywords: Dendritic cells; immunology; periodontitis.

Figure 1

Microbial-dendritic cell (DC) interactions in diseased tissues of periodontitis. DCs recognize and uptake dysbiotic invasive pathogen Porphyromonas gingivalis by a combination of TLR2 and DC-SIGN. DCs migrate through lamina propria (LP) and undergo maturation process and acquire migratory profile. Semi-mature DCs ‘stall’ in the tissues, while fully mature DCs migrate to secondary lymphoid organs (SLO) to present antigens in the context of MHC molecules to T cells and activate the adaptive immune response. As maturing DCs efflux from tissues, blood inflammatory DCs and monocytes migrate into the tissues and differentiate into DCs to replace migrating DCs and maintain proper DCs homeostasis.

Figure 2

DC subsets in human periodontal tissue. Langerhans cells (LC) infiltrate the oral epithelium (EP). The lamina propria (LP) is infiltrated by mature DCs, where they form oral lymphoid foci (OLF) with CD4⁺ T cells resulting in T cell activation and cytokines secretion.

Figure 3

Role of mature DC-CD4+ T cells clusters in osteoclastogenic response. Mature CD83+ MHCII+ DCs in lamina propria (LP) engage with CD4+ T cells and elicit destructive recall responses. Mature DCs and other antigen presenting cells (APCs) release IL-6, TNFα, IL-1β, and IL-23, promoting differentiation of T cells into IL-17A+ Th17 cells. Th17 cells express RANK-L, release IL-17A, IL-17F, and IFN which promote differentiation of preosteoclasts into Trap+ osteoclasts.