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GAS6 is a key homeostatic immunological regulator of host-commensal interactions
in the oral mucosa
#MMPMID28049839
Nassar M
; Tabib Y
; Capucha T
; Mizraji G
; Nir T
; Pevsner-Fischer M
; Zilberman-Schapira G
; Heyman O
; Nussbaum G
; Bercovier H
; Wilensky A
; Elinav E
; Burstyn-Cohen T
; Hovav AH
Proc Natl Acad Sci U S A
2017[Jan]; 114
(3
): E337-E346
PMID28049839
show ga
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.
|Animals
[MESH]
|Dysbiosis/metabolism
[MESH]
|Epithelial Cells/metabolism
[MESH]
|Homeostasis/*physiology
[MESH]
|Immunity, Innate/immunology
[MESH]
|Inflammation/metabolism
[MESH]
|Intercellular Signaling Peptides and Proteins/*metabolism
[MESH]
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