title: GAS6 is a key homeostatic immunological regulator of host-commensal interactions in the oral mucosa.
abstract: The oral epithelium contributes to innate immunity and oral mucosal homeostasis, which is critical for preventing local inflammation and the associated adverse systemic conditions. Nevertheless, the mechanisms by which the oral epithelium maintains homeostasis are poorly understood. Here, we studied the role of growth arrest specific 6 (GAS6), a ligand of the TYRO3-AXL-MERTK (TAM) receptor family, in regulating oral mucosal homeostasis. Expression of GAS6 was restricted to the outer layers of the oral epithelium. In contrast to protein S, the other TAM ligand, which was constitutively expressed postnatally, expression of GAS6 initiated only 3-4 wk after birth. Further analysis revealed that GAS6 expression was induced by the oral microbiota in a myeloid differentiation primary response gene 88 (MyD88)-dependent fashion. Mice lacking GAS6 presented higher levels of inflammatory cytokines, elevated frequencies of neutrophils, and up-regulated activity of enzymes, generating reactive nitrogen species. We also found an imbalance in Th17/Treg ratio known to control tissue homeostasis, as Gas6-deficient dendritic cells preferentially secreted IL-6 and induced Th17 cells. As a result of this immunological shift, a significant microbial dysbiosis was observed in Gas6-/-mice, because anaerobic bacteria largely expanded by using inflammatory byproducts for anaerobic respiration. Using chimeric mice, we found a critical role for GAS6 in epithelial cells in maintaining oral homeostasis, whereas its absence in hematopoietic cells synergized the level of dysbiosis. We thus propose GAS6 as a key immunological regulator of host-commensal interactions in the oral epithelium.
authors.affiliation: Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University, Jerusalem 91120, Israel.
authors.forename: Maria
authors.initials: M
authors.lastname: Nassar
authors.affiliation: Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University, Jerusalem 91120, Israel.
authors.forename: Yaara
authors.initials: Y
authors.lastname: Tabib
authors.affiliation: Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University, Jerusalem 91120, Israel.
authors.forename: Tal
authors.initials: T
authors.lastname: Capucha
authors.affiliation: Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University, Jerusalem 91120, Israel.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Mizraji
authors.affiliation: Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University, Jerusalem 91120, Israel.
authors.forename: Tsipora
authors.initials: T
authors.lastname: Nir
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Meirav
authors.initials: M
authors.lastname: Pevsner-Fischer
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Gili
authors.initials: G
authors.lastname: Zilberman-Schapira
authors.affiliation: Department of Periodontology, Faculty of Dental Medicine, Hadassah Medical Center, Jerusalem 91120, Israel.
authors.forename: Oded
authors.initials: O
authors.lastname: Heyman
authors.affiliation: Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University, Jerusalem 91120, Israel.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nussbaum
authors.affiliation: Department of Microbiology and Molecular Genetics, Faculty of Medicine, Hebrew University, Jerusalem 91120, Israel.
authors.forename: Herve
authors.initials: H
authors.lastname: Bercovier
authors.affiliation: Department of Periodontology, Faculty of Dental Medicine, Hadassah Medical Center, Jerusalem 91120, Israel.
authors.forename: Asaf
authors.initials: A
authors.lastname: Wilensky
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Elinav
authors.affiliation: Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University, Jerusalem 91120, Israel; avihaih@ekmd.huji.ac.il talbu@ekmd.huji.ac.il.
authors.forename: Tal
authors.initials: T
authors.lastname: Burstyn-Cohen
authors.affiliation: Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University, Jerusalem 91120, Israel; avihaih@ekmd.huji.ac.il talbu@ekmd.huji.ac.il.
authors.forename: Avi-Hai
authors.initials: AH
authors.lastname: Hovav
mesh_terms: D000818:Animals; D064806:Dysbiosis / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D007113:Immunity, Innate / Q000276:immunology; D007249:Inflammation / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D015850:Interleukin-6; D051379:Mice; D008810:Mice, Inbred C57BL; D009061:Mouth Mucosa / Q000378:metabolism*; D022423:Myeloid Cells / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D017293:Protein S / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D000076202:c-Mer Tyrosine Kinase / Q000378:metabolism; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D053594:Myeloid Differentiation Factor 88; D017293:Protein S; D026361:Reactive Nitrogen Species; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
keywords: GAS6; TAM; homeostasis; microbiota; oral mucosa