Human neutrophils and oral microbiota: a constant tug-of-war between a harmonious and a discordant coexistence

Abstract

Neutrophils are a major component of the innate host response, and the outcome of the interaction between the oral microbiota and neutrophils is a key determinant of oral health status. The composition of the oral microbiome is very complex and different in health and disease. Neutrophils are constantly recruited to the oral cavity, and their protective role is highlighted in cases where their number or functional responses are impeded, resulting in different forms of periodontal disease. Periodontitis, one of the more severe and irreversible forms of periodontal disease, is a microbial-induced chronic inflammatory disease that affects the gingival tissues supporting the tooth. This chronic inflammatory disease is the result of a shift of the oral bacterial symbiotic community to a dysbiotic more complex community. Chronic inflammatory infectious diseases such as periodontitis can occur because the pathogens are able to evade or disable the innate immune system. In this review, we discuss how human neutrophils interact with both the symbiotic and the dysbiotic oral community; an understanding of which is essential to increase our knowledge of the periodontal disease process.

Keywords: neutrophils; periodontitis; symbiotic and dysbiotic oral community.

Figure 1

A schematic of the host response in a healthy and diseased periodontium. The local oral microbiota of a healthy periodontal site (left) is characterized by low bacterial diversity and quantity. In this homeostatic scenario, the symbiotic biofilm enhances the recruitment of neutrophils which mount a controlled acute inflammatory response. However, in the case of periodontitis (right) genetic predisposing conditions of the host, and/or environmental risk factors favor the colonization of exogenous pathogens, which results in an increase in bacterial diversity, formation and overgrowth of a dysbiotic bacterial biofilm, with massive recruitment and neutrophil infiltration invading the gingival epithelium, and the crevicular fluid. The result of this chronic inflammation involves both the innate and adaptive immune cells which results in periodontal lesions (right, and inset) with connective tissue and alveolar bone destruction

Figure 2

Neutrophil response in periodontal health and disease. (A) A symbiotic microbial community adheres to the gingival epithelial cells (GECs). As the bacterial burden increases, neutrophils regularly exit the blood stream entering the connective tissue layer beneath the epithelium. Some of these neutrophils will transverse the epithelium to kill some of the associated microbes—reducing the bacteria concentration. This process occurs without inflammation or tissue damage. (B) Following environmental stresses (smoking, poor diet, injury etc.) the keystone pathogen, Porphyromonas gingivalis, can colonize the symbiotic microbial community. Following colonization, the GECs are invaded by P. gingivalis which shuts down the IL-8 production via SerB resulting in local chemokine paralysis. Neutrophils enter the connective tissue, but are not initially directed to the infection. This causes many neutrophils to accumulate in the connective tissue. As some neutrophils traverse the epithelium in late infection, their killing mechanisms are hindered by multiple mechanisms including TLR2/C5aR crosstalk. Lipopolysaccharide (LPS) from P. gingivalis inhibits apoptosis of neutrophils leading to excessive inflammation, and P. gingivalis' gingipains may increase inflammation by accumulation of sTREM-1. Neutrophil degranulation, reactive oxygen species (ROS) production and NETosis damage GECs resulting in cytokine (TNF-α, IL-6, and IL-1β) secretion by the GECs and the activated neutrophils. This further activates circulating neutrophils and results in large neutrophil chemotaxis to the periodontal plaque. A cycle of tissue damage followed by neutrophil activation/recruitment followed by more tissue damage ensues. Inflammophilic pathobionts take advantage of the inflammation while susceptible commensals are eradicated