Gingival Tissue Inflammation Promotes Increased Matrix Metalloproteinase-12 Production by CD200Rlow Monocyte-Derived Cells in Periodontitis

Abstract

Irreversible tissue recession in chronic inflammatory diseases is associated with dysregulated immune activation and production of tissue degradative enzymes. In this study, we identified elevated levels of matrix metalloproteinase (MMP)-12 in gingival tissue of patients with the chronic inflammatory disease periodontitis (PD). The source of MMP12 was cells of monocyte origin as determined by the expression of CD14, CD68, and CD64. These MMP12-producing cells showed reduced surface levels of the coinhibitory molecule CD200R. Similarly, establishing a multicellular three-dimensional model of human oral mucosa with induced inflammation promoted MMP12 production and reduced CD200R surface expression by monocyte-derived cells. MMP12 production by monocyte-derived cells was induced by CSF2 rather than the cyclooxygenase-2 pathway, and treatment of monocyte-derived cells with a CD200R ligand reduced CSF2-induced MMP12 production. Further, MMP12-mediated degradation of the extracellular matrix proteins tropoelastin and fibronectin in the tissue model coincided with a loss of Ki-67, a protein strictly associated with cell proliferation. Reduced amounts of tropoelastin were confirmed in gingival tissue from PD patients. Thus, this novel association of the CD200/CD200R pathway with MMP12 production by monocyte-derived cells may play a key role in PD progression and will be important to take into consideration in the development of future strategies to diagnose, treat, and prevent PD.

S100A12 Expression Is Modulated During Monocyte Differentiation and Reflects Periodontitis Severity

“…It is worth noting that the secreted levels in the cultures were somewhat similar to that of differentiated macrophages in monoculture. Our group previously reported that monocyte-derived cells in the model are CD64 + and display increased expression of CD14, CD68, and CD163 during their differentiation, evidencing a macrophage-like phenotype (20). Previous reports have shown that both TLR ligands and IFN-γ induce S100A12 expression in monocytes and/or macrophages (12,36,37).…”

“…A 3D oral tissue model was set up containing epithelial cells (TERT-immortalized normal human oral keratinocyte line OKF6/TERT-2, kindly provided by J. Rheinwald) (23), primary fibroblasts (24), and monocytes as previously described (20). Briefly, 3-µm pore size transwell inserts were placed in 6-well plates and coated with a mixture of bovine type I collagen (PureCol, Cell Systems, Troisdorf, Germany) and DMEM (GE Healthcare Life Sciences, Uppsala, Sweden).…”

“…Its pathogenesis involves a complex interplay between the dysbiotic microbiota and the host immuneinflammatory response (19), where myeloid cells play a critical role in the periodontal injury. These cells infiltrate the gingival tissue during disease, undermine oral mucosa integrity through the production of matrix metalloproteinase (MMP)-12 (20) and contribute to the alveolar bone resorption (21). It has been shown that S100A12 levels in saliva are associated with periodontal disease (22).…”

IL‑18 promotes the secretion of matrix metalloproteinases in human periodontal ligament fibroblasts by activating NF‑κB signaling

“…MMPs are a family of Zn 2+ -containing neutral proteolytic enzymes that degrade extracellular matrix (ECM). Human MMPs are classified as collagenases, gelatinases, matrix lysins, membrane-type MMPs and other MMPs (14,15). The direct effects of MMPs in periodontal tissue destruction and degradation are involved in the development of periodontitis.…”

Characteristic of Innate Component of Local Immunity of in Periodontium Tissues of Rats After Tooth Extraction in Diabetes Mellitus by Cd 68 Expression Indices

“…Показана можливість трансформації М1 фенотипу в М2 при зміні спектра стимулюючих цитокінів. Одна з відмінностей між М2 і М1 полягає в тому, що в М2 продуктами метаболізму аргініну є орнітин і поліаміни, тоді як у М1 -оксид азоту та цитрулін [5]. Доведено, що паралельне визначення показників експресії CD68 та індуцибельної ізоформи ферменту синтази оксиду азоту (iNOS) дає можливість оцінити поляризацію макрофагів у бік «класично» активованих М1 із значним утворення фактору некрозу пухлин-α, оксиду азоту та інших прозапальних цитокінів та медіаторів [6].…”