Toll-Like Receptor Signaling and Immune Regulatory Lymphocytes in Periodontal Disease

Abstract

Periodontitis is known to be initiated by periodontal microbiota derived from biofilm formation. The microbial dysbiotic changes in the biofilm trigger the host immune and inflammatory responses that can be both beneficial for the protection of the host from infection, and detrimental to the host, causing tissue destruction. During this process, recognition of Pathogen-Associated Molecular Patterns (PAMPs) by the host Pattern Recognition Receptors (PRRs) such as Toll-like receptors (TLRs) play an essential role in the host-microbe interaction and the subsequent innate as well as adaptive responses. If persistent, the adverse interaction triggered by the host immune response to the microorganisms associated with periodontal biofilms is a direct cause of periodontal inflammation and bone loss. A large number of T and B lymphocytes are infiltrated in the diseased gingival tissues, which can secrete inflammatory mediators and activate the osteolytic pathways, promoting periodontal inflammation and bone resorption. On the other hand, there is evidence showing that immune regulatory T and B cells are present in the diseased tissue and can be induced for the enhancement of their anti-inflammatory effects. Changes and distribution of the T/B lymphocytes phenotype seem to be a key determinant of the periodontal disease outcome, as the functional activities of these cells not only shape up the overall immune response pattern, but may directly regulate the osteoimmunological balance. Therefore, interventional strategies targeting TLR signaling and immune regulatory T/B cells may be a promising approach to rebalance the immune response and alleviate bone loss in periodontal disease. In this review, we will examine the etiological role of TLR signaling and immune cell osteoclastogenic activity in the pathogenesis of periodontitis. More importantly, the protective effects of immune regulatory lymphocytes, particularly the activation and functional role of IL-10 expressing regulatory B cells, will be discussed.

Keywords: Breg; RANKL; TLR; Treg; periodontal disease.

Figure 1

Immune responses directly contribute to the pathogenesis of periodontitis. A balanced pro- and anti-inflammatory responses need to be achieved to maintain tissue homeostasis. If the pro-inflammatory subtype of cells is predominantly persisted, it is inclined towards tissue destruction and bone resorption. Conversely, if the anti-inflammatory and pro-resolving lineages are predominantly developed in a timely fashion, inflammation will be controlled, and tissues will be repaired or regenerated.

Figure 2

Potential immunological approaches to interfere with immune cell-mediated, RANKL-dependent periodontal bone resorption. The central target of these approaches is the inhibition of RANKL expression, secretion and interaction with RANK on osteoclast precursor cells. APC, antigen-presenting cell; CD40 L, CD40 ligand; CRAC, Ca2+ release-activated Ca2+ channels; IL-10, interleukin-10; mRANKL, membrane-bound RANKL; sRANKL, soluble RANKL; NFAT, nuclear factor of activated T cells; OPG, osteoprotegerin; RANK, receptor activator of nuclear factor κB; RANKL, receptor activator of nuclear factor κB ligand; TRAF6, tumor necrosis factor-receptor associated factor 6.

Figure 3

Promoting local B10 function to curtail immune-mediated periodontal inflammation and bone loss. In periodontal disease, activated Th1 and Th17 cells produce pro-inflammatory cytokines that contribute to tissue damage. Both activated T and B cells produce RANKL, which leads to osteoclast activation and alveolar bone resorption. B10 cell activation and expansion promote IL-10 secretion and promote CD4⁺FOXP3⁺Treg activation, inhibit Th1/Th17 cells and RANKL⁺ T/B cells activation, which inhibit inflammation and RANKL production, eventually alleviating periodontal bone resorption.