The cytokine network involved in the host immune response to periodontitis

Abstract

Periodontitis is an inflammatory disease involving the destruction of both soft and hard tissue in the periodontal region. Although dysbiosis of the local microbial community initiates local inflammation, over-activation of the host immune response directly activates osteoclastic activity and alveolar bone loss. Many studies have reported on the cytokine network involved in periodontitis and its crucial and pleiotropic effect on the recruitment of specific immunocytes, control of pathobionts and induction or suppression of osteoclastic activity. Nonetheless, particularities in the stimulation of pathogens in the oral cavity that lead to the specific and complex periodontal cytokine network are far from clarified. Thus, in this review, we begin with an up-to-date aetiological hypothesis of periodontal disease and summarize the roles of cytokines in the host immune response. In addition, we also summarize the latest cytokine-related therapeutic measures for periodontal disease.

Fig. 1

The homeostasis of periodontal tissue, pathogenesis of chronic periodontitis and roles of the involved cytokines. In a healthy state, local challenge and a mild host immune response are balanced. Both the commensal microbiota and mechanical stimulation caused by mastication participate in the training of local mucosal immunity. In this state, there is an appropriate number of infiltrating neutrophils in the gingival sulcus, as well as some resident immune cells in the gingival tissue, including Th17 cells and innate lymphoid cells. However, if the immune pathogenicity of the local microbiota is elevated by the colonization of keystone pathogens, which over-activate the host immune response, tissue destruction is initiated. The interaction between the microbiota and all host cells leads to the first wave of cytokine secretion (1), which mainly participates in the amplification of the pro-inflammatory cytokine cascade and the recruitment, activation and differentiation of specific immune cells. In addition, a group of cytokines (2) closely related to the differentiation of a specific subset of lymphocytes are secreted by MNPs and APCs after stimulation by the microbiome. Each of these cell subsets secretes a certain pattern of cytokines, which might act as the positive-feedback factor or direct effector (3), eventually leading to tissue destruction

Fig. 2

The cytokine network in the pathogenesis of periodontitis. In this figure, the effects of cytokines in the host immune response are shown at the level of intercellular interactions. Briefly, well-established pro-inflammatory cytokines from IL-1, IL-6 and TNF families are secreted by host periodontal cells and immunocytes after stimulation by pathobionts, which activates and recruits specific immune cell subsets and causes direct tissue damage. Then, naive T cells and B cells differentiate into mature T cells or plasma cells under the action of specific cytokines and further activate or promote other effector cells, such as osteoclasts and neutrophils, which exert pro-inflammatory or anti-inflammatory effects by secreting cell-specific cytokine clusters. Among these cell subsets, Th1 and Treg cells mainly act as protectors, while Th2/B and Th17 cells exert complex effects that may lead to tissue destruction or protection under certain circumstances (full lines: the effect of cytokines on cells and the interactions between cells; dashed lines: the secretion of cytokines)

Fig. 3

Pro-inflammatory cytokines, related receptor complexes and downstream signalling pathways. Most IL-1 (represented by IL-1, IL-18 and IL-33), IL-6 and TNF family members have pleiotropic effects on lymphocyte promotion and tissue destruction and act as pro-inflammatory cytokines. By binding to their corresponding receptor, IL-1 family members mainly activate transcription factors related to T cell activation and pro-inflammatory cytokine secretion, and IL-6 mainly mediates B cell activation. Depending on the state of key transduction proteins, the binding between TNF family members and their related receptors can lead to very different cell fates that include death (apoptosis and necroptosis) or life (secretion of pro-inflammatory and osteoclastogenic factors) and both lead to the destruction of periodontal tissue

Fig. 4

Cytokines that are closely related to certain groups of T lymphocytes. Most of the remaining cytokines are closely related to the differentiation and/or effects of specific immune cell subsets. Under stimulation by certain inflammatory cytokines, naive CD4⁺ T cells differentiate towards multiple directions, including Th1 (IL-12) and Treg (IL-2 and TGF-β) cells, which mainly have protective effects, and Th17 (IL-23) and Th2 (IL-4) cells, which mainly have pleiotropic effects. The signalling pathways downstream of IL-17 (secreted by Th17 cells) and IL-10 (secreted by Treg cells) are specific and of special significance to the periodontal host immune response, as shown in this figure