Abstract
Growth arrest-specific 6 (GAS6) expressed by oral epithelial cells and dendritic cells (DCs) was shown to play a critical role in the maintenance of oral mucosal homeostasis. In this study, we demonstrate that the induction of pathogen-specific oral adaptive immune responses is abrogated in Gas6−/− mice. Further analysis revealed that GAS6 induces simultaneously both pro- and anti-inflammatory regulatory pathways upon infection. On one hand, GAS6 upregulates expression of adhesion molecules on blood vessels, facilitating extravasation of innate inflammatory cells to the oral mucosa. GAS6 also elevates expression of CCL19 and CCL21 chemokines and enhances migration of oral DCs to the lymph nodes. On the other hand, expression of pro-inflammatory molecules in the oral mucosa are downregulated by GAS6. Moreover, GAS6 inhibits DC maturation and reduces antigen presentation to T cells by DCs. These data suggest that GAS6 facilitates bi-directional trans-endothelial migration of inflammatory cells and DCs, whereas inhibiting mucosal activation and T-cell stimulation. Thus, the orchestrated complex activity of GAS6 enables the development of a rapid and yet restrained mucosal immunity to oral pathogens.
Highlights
The oral cavity is a unique anatomical structure composed of soft and hard tissues, which are continuously exposed to the microbiota
We recently reported the critical role of growth arrest-specific 6 (GAS6) protein in regulating oral mucosal homeostasis [3]
We examined the induction of oral mucosal immune responses by analyzing the gingiva of the infected mice
Summary
The oral cavity is a unique anatomical structure composed of soft and hard tissues, which are continuously exposed to the microbiota. This task, is not trivial and oral pathogens such as Porphyromonas gingivalis can cause a disease by inducing microbial dysbiosis [1] Such an alteration in the composition of oral microbiota results in the development of destructive local immunity, which is associated with systemic adverse complications [2]. GAS6 expressed by dendritic cells (DCs) was found to restrain IL-6 production favoring the generation of T regulatory (Treg) over Th17 cells, further facilitating tolerogenic immune responses against the oral microbiota [3] Whereas these findings high light a central role of GAS6/AXL signaling in regulating oral mucosal homeostasis, targeting the GAS6/AXL axis by pathogens might induce dysbiosis and subsequent oral pathology. The unrestrained IFN-α secretion due to the absence of negative regulation by GAS6 and AXL enables the development of excessive Th1-type inflammatory responses which enhance alveolar bone loss [6]
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