Chapter Five - Emerging avenues linking myeloid-derived suppressor cells to periodontal disease

The periodontium, also known as periodontal tissue, is a complex structure composed of the tissues that surround and support the teeth. These tissues include the gingiva, periodontal ligament (PDL), cementum, and alveolar bone (Guo et al., 2022; Kim et al., 2021). The gingiva is located on the external surface of the periodontium and performs crucial structural functions such as supporting the teeth, in addition to protective and defensive roles to block the entrance of pathogens. The cementum is a hard tissue that surrounds the tooth root and contributes to tooth attachment and maintaining the tooth in an occlusal position. The PDL is considered a soft tissue that stabilizes the teeth and offers resistance during displacement, in addition to distributing occlusal forces. The PDL connects the cementum covering the tooth root to the socket of the alveolar bone (Guo et al., 2022; Kim et al., 2021). The alveolar bone possesses several unique characteristics that are unlike those of other skeletal bones. For example, this bone retains the teeth and is frequently subjected to strains during mastication. Furthermore, it undergoes a constant cycle of resorption by osteoclasts and new bone formation by osteoblasts during different events such as tooth eruption or chewing (Guo et al., 2022; Omi and Mishina, 2022). Moreover, periodontal tissues can suffer infections and damage, leading to periodontal disease.

Periodontal disease is one of the most common inflammatory conditions and is mostly caused by bacterial infection. It is one of the two most commonly occurring dental illnesses and is considered the sixth most common disease worldwide. Periodontal disease encompasses disorders occurring in periodontal tissue being the main periodontal diseases: gingivitis and periodontitis (Faulkner et al., 2022; Li et al., 2022; Tsuchida and Nakayama, 2022). Recent studies have estimated that periodontitis affects 45%–50% of the world's population and the prevalence of periodontal disease is projected to increase due to the aging population, which constitutes an important public health concern (González-Ramírez et al., 2022). Gingivitis is the mildest form of periodontal disease, which involves inflammation of the gingival tissue. However, if left unattended, gingivitis can lead to periodontitis, an inflammatory disease characterized by soft tissue damage and the progressive destruction of the PDL and alveolar bone. This, in turn, can ultimately lead to tooth loss, thus affecting the quality of life of patients (Faulkner et al., 2022; Jiang et al., 2022). Additionally, periodontitis has been associated with inflammatory disorders such as cardiovascular disease, type 2 diabetes, rheumatoid arthritis, inflammatory bowel disease, Alzheimer's disease, and certain types of cancer Previous studies have suggested that periodontitis could aggravate these conditions by inducing systemic inflammation through the dissemination of periodontal bacteria/bacterial components and/or the release of inflammatory molecules from periodontal tissue to the blood. Additionally, periodontal bacteria could reach distant tissues by traveling through the oropharyngeal and orodigestive tracts (Hajishengallis and Chavakis, 2021). In periodontal disease, periodontal tissue damage has been linked to inflammatory and immune responses of the host to the accumulation of oral biofilms, as well as alterations in the composition of oral microbial communities (i.e., dysbiosis). Local cells and resident immune cells in periodontal tissues produce inflammatory molecules in response to bacterial dysbiosis, thus stimulating the dilation of local blood vessels. Furthermore, cytokines and chemokines promote recruitment of inflammatory cells into the tissue. The number of neutrophils increases and macrophages, lymphocytes, plasma cells, and mast cells are also found in the connective tissue. Plasma cells, macrophages, and T and B lymphocytes are dominant during the establishment of the acquired immune response. Without an effective and proper resolution of the inflammatory process and chronic persistence of the stimulus, the immune response can lead to dominant activity of osteoclast (multinucleated giant cells originating from monocyte/macrophage cells) resulting in alveolar bone resorption (Jiang et al., 2022; Kinane et al., 2017). Inflammatory mediators also play important roles in periodontal disease. Interleukin (IL)-1β, tumor necrosis factor α (TNF-α), and prostaglandin E2 (PGE2) promote the expression of proteolytic enzymes such as matrix metalloproteinases, resulting in periodontal tissue destruction. Additionally, bacterial molecules can also directly damage the cells of periodontal tissues. Macrophage colony-stimulating factor (M-CSF, also known as CSF1) and receptor activator of nuclear factor kappa-B (NF-κB) ligand (RANKL) are essential mediators of osteoclast activation. RANKL binds to the RANK receptor expressed in progenitor and mature osteoclasts. Furthermore, osteoprotegerin (OPG), a soluble decoy receptor for RANKL, impedes RANK/RANKL binding, thus inhibiting osteoclastogenesis. IL-6 and TNF-α stimulate to osteocytes to produce RANKL, which increases the RANKL/OPG ratio in periodontitis. Moreover, bacterial compounds and inflammatory cytokines present in periodontitis induce the apoptosis of osteocytes, which promotes IL-6 secretion and expression of RANKL, leading to osteoclastogenesis and bone resorption (Kinane et al., 2017; Sirisereephap et al., 2022; Yucel-Lindberg and Båge, 2013).

Myeloid-derived suppressor cells (MDSCs) are immunoregulatory myeloid cells that are thought to be involved in periodontal disease (Valero-Monroy et al., 2016) and have thus been recently analyzed in the context of this disease. MDSCs represent a heterogeneous group of immature myeloid cells derived from hematopoietic precursor cells and exhibit T cell immunosuppressive functions. In chronic inflammatory conditions such as infectious diseases, dysbiosis, autoimmune disorders, or cancer, the constant stimulation of myelopoiesis results in the accumulation of MDSCs (Ma et al., 2022). MDSCs present a large range of phenotypes. Classically, MDSCs have been defined with the markers CD11b and Gr1 in mice, and can be divided into two subpopulations: monocytic (M)-MDSCs, which are defined as CD11b + Ly6ChighLy6G–cells, and granulocytic (G)-MDSCs, which are defined as CD11b + Ly6C−/lowLy6G+ cells.. However, MDSCs are far more complex in humans and diverse phenotypes have been described in different tumors and infectious diseases. Human MDSCs have been characterized by the expression of the common myeloid markers CD33 or CD11b, as well as the lack of mature myeloid cell markers such as HLA-DR (Wang et al., 2021). MDSCs perform different immunoregulatory functions. For example, they can stimulate the de novo generation of regulatory T cells through a process mediated by interferon (IFN)-gamma and IL-10. Moreover, MDSCs can produce transforming growth factor (TGF)-β and IL-10 to exert immunosuppressive effects on effector T cells. Moreover, MDSCs can secrete reactive oxygen species (ROS) such as superoxide anions, hydroxyl radicals, hydrogen peroxide, and singlet oxygen. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)1, NOX2, NOX3, and NOX4 transfer electrons from NADPH to oxygen and produce superoxide radicals. These enzymes are involved in the primary ROS production pathway of MDSCs. ROS are toxic to cells and can contribute to the elimination of T cells (Groth et al., 2019). Furthermore, MDSCs can produce reactive nitrogen species (RNS) [primarily nitric oxide (NO)] through the activation of inducible NO synthase (iNOS). NO can react with superoxide to produce peroxynitrites, which promote the apoptosis of T cells and the nitration of the T-cell receptor (TCR), thus inhibiting T cell activation (Groth et al., 2019; Ma et al., 2022). L-arginine is an amino acid that greatly contributes to the function of T cells. However, this amino acid can be depleted by MDSCs through different mechanisms. For example, iNOS participates in its depletion by catalyzing the conversion of L-arginine to NO and L-citrulline. Arginase-1, another enzyme highly expressed by MDSCs, converts L-arginine to L-ornithine and urea. Moreover, MDSCs can increase the uptake of L-arginine by the CAT-2B transporter. Depletion of L-arginine leads to blockage of T cell proliferation and reduced TCR ζ-chain expression, thus impairing T cell functions. Additionally, MDSCs can deplete cysteine (i.e., an essential amino acid for glutathione and DNA synthesis by T cells) by increasing the uptake of this amino acid through the SLC7A11 transporter. In turn, this not only impairs ROS resistance but also T cell activation (Groth et al., 2019; Leija Montoya et al., 2019; Ma et al., 2022). Recent studies have suggested that the functions of MDSCs could prevent uncontrolled immune responses in situations requiring tolerance. However, in cases of constant tissue damage and chronic inflammation, MDSCs could exacerbate tissue injury and promote inflammation (Sanchez-Pino et al., 2021). This review discusses the most recent advances in the characterization of the biological aspects, subpopulations, and traffic of MDSCs, as well as their immunosuppressive and osteoclastogenic activity in the context of periodontal health and disease and in the presence of important periodontal pathogens.

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