Fig. S7.

A proposed model for the role of GAS6 in maintaining oral mucosal homeostasis. Under homeostatic conditions, 3–4 wk after birth, oral microbiota induces expression of GAS6 in the oral epithelium in a MYD88-dependent pathway, most likely via triggering TLR2/4 known to be expressed on oral epithelial cells. Expression of GAS6 inhibits activation of epithelial cells by microbiota by down-regulating secretion of proinflammatory cytokines and production of free radicals. In addition, GAS6 induces the differentiation of Treg rather than Th17 cells by controlling IL-6 expression in DCs. These conditions favor the colonization of the Firmicutes phylum, particularly Streptococcaceae, hallmarks of microbial homeostasis in the oral mucosa. In the absence of GAS6, the oral epithelium becomes activated and DCs induce Th17 cells, while reducing Treg numbers and function. As a result, the oral mucosa becomes inflamed, resulting in up-regulation of the enzymes, iNOS, NOX1, and DUOX2 in epithelial cells and neutrophils, which generate reactive nitrogen species (NO) and reactive oxygen species (O₂⁻). Respiratory electron acceptors (NO₃⁻) generated as a byproduct of the host inflammatory response support growth of the Proteobacteria phylum and Lactobacillales (Firmicutes) that express nitrate reductase and by anaerobic respiration convert NO₃⁻ to NO₂⁻. Other bacterial populations, Firmicutes (Chlostridia) and Bacteroidetes are also preferentially expanded under inflammatory conditions, whereas the latter phylum contains several important oral pathogens that exist in periodontal inflammation disease.