TY - JOUR
T1 - Aryl hydrocarbon receptor signaling promotes ORMDL3-dependent generation of sphingosine-1-phosphate by inhibiting sphingosine-1-phosphate lyase
AU - Wang, Hsueh Chun
AU - Wong, Tzu Hsuan
AU - Wang, Li Ting
AU - Su, Hsiang Han
AU - Yu, Hsiu Yueh
AU - Wu, Ai Hsuan
AU - Lin, Yu Chun
AU - Chen, Hua Ling
AU - Suen, Jau Ling
AU - Hsu, Shih Hsien
AU - Chen, Li Chen
AU - Zhou, Yufeng
AU - Huang, Shau Ku
N1 - Publisher Copyright:
© 2018, CSI and USTC.
PY - 2019/10/1
Y1 - 2019/10/1
N2 - Aryl hydrocarbon receptor (AhR), a cellular chemical sensor, controls cellular homeostasis, and sphingosine-1-phosphate (S1P), a bioactive intermediate of sphingolipid metabolism, is believed to have a role in immunity and inflammation, but their potential crosstalk is currently unknown. We aimed to determine whether there is a functional linkage between AhR signaling and sphingolipid metabolism. We showed that AhR ligands, including an environmental polycyclic aromatic hydrocarbon (PAH), induced S1P generation, and inhibited S1P lyase (S1PL) activity in resting cells, antigen/IgE-activated mast cells, and mouse lungs exposed to the AhR ligand alone or in combination with antigen challenge. The reduction of S1PL activity was due to AhR-mediated oxidation of S1PL at residue 317, which was reversible by the addition of an antioxidant or in cells with knockdown of the ORMDL3 gene encoding an ER transmembrane protein, whereas C317A S1PL mutant-transfected cells were resistant to the AhR-mediated effect. Furthermore, analysis of AhR ligand-treated cells showed a time-dependent increase of the ORMDL3–S1PL complex, which was confirmed by FRET analysis. This change increased the S1P levels, which in turn, induced mast cell degranulation via S1PR2 signaling. In addition, elevated levels of plasma S1P were found in children with asthma compared to non-asthmatic subjects. These results suggest a new regulatory pathway whereby the AhR–ligand axis induces ORMDL3-dependent S1P generation by inhibiting S1PL, which may contribute to the expression of allergic diseases.
AB - Aryl hydrocarbon receptor (AhR), a cellular chemical sensor, controls cellular homeostasis, and sphingosine-1-phosphate (S1P), a bioactive intermediate of sphingolipid metabolism, is believed to have a role in immunity and inflammation, but their potential crosstalk is currently unknown. We aimed to determine whether there is a functional linkage between AhR signaling and sphingolipid metabolism. We showed that AhR ligands, including an environmental polycyclic aromatic hydrocarbon (PAH), induced S1P generation, and inhibited S1P lyase (S1PL) activity in resting cells, antigen/IgE-activated mast cells, and mouse lungs exposed to the AhR ligand alone or in combination with antigen challenge. The reduction of S1PL activity was due to AhR-mediated oxidation of S1PL at residue 317, which was reversible by the addition of an antioxidant or in cells with knockdown of the ORMDL3 gene encoding an ER transmembrane protein, whereas C317A S1PL mutant-transfected cells were resistant to the AhR-mediated effect. Furthermore, analysis of AhR ligand-treated cells showed a time-dependent increase of the ORMDL3–S1PL complex, which was confirmed by FRET analysis. This change increased the S1P levels, which in turn, induced mast cell degranulation via S1PR2 signaling. In addition, elevated levels of plasma S1P were found in children with asthma compared to non-asthmatic subjects. These results suggest a new regulatory pathway whereby the AhR–ligand axis induces ORMDL3-dependent S1P generation by inhibiting S1PL, which may contribute to the expression of allergic diseases.
KW - Aryl hydrocarbon receptor
KW - ORMDL sphingolipid biosynthesis regulator 3
KW - Sphingosine-1-phosphate
KW - Sphingosine-1-phosphate lyase
UR - http://www.scopus.com/inward/record.url?scp=85044386497&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85044386497&partnerID=8YFLogxK
U2 - 10.1038/s41423-018-0022-2
DO - 10.1038/s41423-018-0022-2
M3 - Article
AN - SCOPUS:85044386497
SN - 1672-7681
VL - 16
SP - 783
EP - 790
JO - Cellular and Molecular Immunology
JF - Cellular and Molecular Immunology
IS - 10
ER -