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Aryl hydrocarbon receptor signaling promotes ORMDL3-dependent generation of sphingosine-1-phosphate by inhibiting sphingosine-1-phosphate lyase

Cellular & Molecular Immunology volume 16, pages 783–790 (2019)Cite this article

A Correction to this article was published on 16 May 2018

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Abstract

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.

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  • 16 May 2018

    In this article, published online 23 March 2018, the affiliation 10 of Zhou Y was incorrect. The affiliation should be “Children’s Hospital and Institute of Biomedical Sciences, Fudan University. Key Laboratory of Neonatal Disease, Ministry of Health, 201102, Shanghai, China.” The authors regret the errors.

References

  1. Nguyen, N. T., Hanieh, H., Nakahama, T. & Kishimoto, T. The roles of aryl hydrocarbon receptor in immune responses. Int. Immunol. 25, 335–43 (2013).

    Article  CAS  Google Scholar 

  2. Sibilano, R., Pucillo, C. E. & Gri, G. Allergic responses and aryl hydrocarbon receptor novel pathway of mast cell activation. Mol. Immunol. 63, 69–73 (2015).

    Article  CAS  Google Scholar 

  3. Quintana, F. J. The aryl hydrocarbon receptor: a molecular pathway for the environmental control of the immune response. Immunology 138, 183–9 (2013).

    Article  CAS  Google Scholar 

  4. Veldhoen, M., Hirota, K., Westendorf, A. M., Buer, J., Dumoutier, L. & Renauld, J. C. et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453, 106–9 (2008).

    Article  CAS  Google Scholar 

  5. Zhou, Y., Tung, H. Y., Tsai, Y. M., Hsu, S. C., Chang, H. W. & Kawasaki, H. et al. Aryl hydrocarbon receptor controls murine mast cell homeostasis. Blood 121, 3195–204 (2013).

    Article  CAS  Google Scholar 

  6. Wang, H. C., Zhou, Y. & Huang, S. K. SHP-2 phosphatase controls aryl hydrocarbon receptor-mediated ER stress response in mast cells. Arch. Toxicol. 91, 1739–48 (2017).

    Article  CAS  Google Scholar 

  7. Breslow, D. K., Collins, S. R., Bodenmiller, B., Aebersold, R., Simons, K. & Shevchenko, A. et al. Orm family proteins mediate sphingolipid homeostasis. Nature 463, 1048–53 (2010).

    Article  CAS  Google Scholar 

  8. Oyeniran, C., Sturgill, J. L., Hait, N. C., Huang, W. C., Avni, D. & Maceyka, M. et al. Aberrant ORM (yeast)-like protein isoform 3 (ORMDL3) expression dysregulates ceramide homeostasis in cells and ceramide exacerbates allergic asthma in mice. J. Allergy Clin. Immunol. 136, 1035–46 (2015).

    Article  CAS  Google Scholar 

  9. Kiefer, K., Carreras-Sureda, A., Garcia-Lopez, R., Rubio-Moscardo, F., Casas, J. & Fabrias, G. et al. Coordinated regulation of the orosomucoid-like gene family expression controls de novo ceramide synthesis in mammalian cells. J. Biol. Chem. 290, 2822–30 (2015).

    Article  CAS  Google Scholar 

  10. Zhakupova, A., Debeuf, N., Krols, M., Toussaint, W., Vanhoutte, L. & Alecu, I. et al. ORMDL3 expression levels have no influence on the activity of serine palmitoyltransferase. FASEB J. 30, 4289–300 (2016).

    Article  CAS  Google Scholar 

  11. Siow, D., Sunkara, M., Dunn, T. M., Morris, A. J. & Wattenberg, B. ORMDL/serine palmitoyltransferase stoichiometry determines effects of ORMDL3 expression on sphingolipid biosynthesis. J. Lipid Res. 56, 898–908 (2015).

    Article  CAS  Google Scholar 

  12. Miller, M., Rosenthal, P., Beppu, A., Gordillo, R. & Broide, D. H. Oroscomucoid such as protein 3 (ORMDL3) transgenic mice have reduced levels of sphingolipids including sphingosine-1-phosphate and ceramide. J. Allergy Clin. Immunol. 139, 1373–6 (2017).

    Article  CAS  Google Scholar 

  13. Moffatt, M. F., Kabesch, M., Liang, L., Dixon, A. L., Strachan, D. & Heath, S. et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 448, 470–3 (2007).

    Article  CAS  Google Scholar 

  14. Balantic, M., Rijavec, M., Flezar, M., Camlek, T., Hudoklin, I. & Kosnik, M. et al. A polymorphism in ORMDL3 is associated not only with asthma without rhinitis but also with chronic obstructive pulmonary disease. J. Investig. Allergol. Clin. Immunol. 23, 256–61 (2013).

    CAS  PubMed  Google Scholar 

  15. Barrett, J. C., Hansoul, S., Nicolae, D. L., Cho, J. H., Duerr, R. H. & Rioux, J. D. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat. Genet. 40, 955–62 (2008).

    Article  CAS  Google Scholar 

  16. McGovern, D. P., Gardet, A., Torkvist, L., Goyette, P., Essers, J. & Taylor, K. D. et al. Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat. Genet. 42, 332–7 (2010).

    Article  CAS  Google Scholar 

  17. Kurreeman, F. A., Stahl, E. A., Okada, Y., Liao, K., Diogo, D. & Raychaudhuri, S. et al. Use of a multiethnic approach to identify rheumatoid- arthritis-susceptibility loci, 1p36 and 17q12. Am. J. Hum. Genet. 90, 524–32 (2012).

    Article  CAS  Google Scholar 

  18. Cantero-Recasens, G., Fandos, C., Rubio-Moscardo, F., Valverde, M. A. & Vicente, R. The asthma-associated ORMDL3 gene product regulates endoplasmic reticulum-mediated calcium signaling and cellular stress. Hum. Mol. Genet. 19, 111–21 (2010).

    Article  CAS  Google Scholar 

  19. Miller, M., Tam, A. B., Cho, J. Y., Doherty, T. A., Pham, A. & Khorram, N. et al. ORMDL3 is an inducible lung epithelial gene regulating metalloproteases, chemokines, OAS, and ATF6. Proc. Natl Acad. Sci. USA 109, 16648–53 (2012).

    Article  CAS  Google Scholar 

  20. Miller, M., Tam, A. B., Mueller, J. L., Rosenthal, P., Beppu, A. & Gordillo, R. et al. Cutting edge: targeting epithelial ORMDL3 increases, rather than reduces, airway responsiveness and is associated with increased sphingosine-1-phosphate. J. Immunol. 198, 3017–22 (2017).

    Article  CAS  Google Scholar 

  21. Miller, M., Rosenthal, P., Beppu, A., Mueller, J. L., Hoffman, H. M. & Tam, A. B. et al. ORMDL3 transgenic mice have increased airway remodeling and airway responsiveness characteristic of asthma. J. Immunol. 192, 3475–87 (2014).

    Article  CAS  Google Scholar 

  22. Rosenfeldt, H. M., Amrani, Y., Watterson, K. R., Murthy, K. S., Panettieri, R. A. Jr. & Spiegel, S. Sphingosine-1-phosphate stimulates contraction of human airway smooth muscle cells. FASEB J. 17, 1789–99 (2003).

    Article  CAS  Google Scholar 

  23. Worgall, T. S., Veerappan, A., Sung, B., Kim, B. I., Weiner, E. & Bholah, R. et al. Impaired sphingolipid synthesis in the respiratory tract induces airway hyperreactivity. Sci. Transl. Med. 5, 186ra167 (2013).

    Article  Google Scholar 

  24. Maceyka, M. & Spiegel, S. Sphingolipid metabolites in inflammatory disease. Nature 510, 58–67 (2014).

    Article  CAS  Google Scholar 

  25. Olivera, A. & Rivera, J. An emerging role for the lipid mediator sphingosine-1-phosphate in mast cell effector function and allergic disease. Adv. Exp. Med. Biol. 716, 123–42 (2011).

    Article  CAS  Google Scholar 

  26. Serra, M. & Saba, J. D. Sphingosine 1-phosphate lyase, a key regulator of sphingosine 1-phosphate signaling and function. Adv. Enzyme Regul. 50, 349–62 (2010).

    Article  Google Scholar 

  27. Oskeritzian, C. A., Price, M. M., Hait, N. C., Kapitonov, D., Falanga, Y. T. & Morales, J. K. et al. Essential roles of sphingosine-1-phosphate receptor 2 in human mast cell activation, anaphylaxis, and pulmonary edema. J. Exp. Med. 207, 465–74 (2010).

    Article  CAS  Google Scholar 

  28. Jolly, P. S., Bektas, M., Olivera, A., Gonzalez-Espinosa, C., Proia, R. L. & Rivera, J. et al. Transactivation of sphingosine-1-phosphate receptors by Fc epsilon RI triggering is required for normal mast cell degranulation and chemotaxis. J. Exp. Med. 199, 959–70 (2004).

    Article  CAS  Google Scholar 

  29. Oskeritzian, C. A., Milstien, S. & Spiegel, S. Sphingosine-1-phosphate in allergic responses, asthma and anaphylaxis. Pharmacol. Ther. 115, 390–9 (2007).

    Article  CAS  Google Scholar 

  30. Zhan, X. & Desiderio, D. M. Nitroproteins from a human pituitary adenoma tissue discovered with a nitrotyrosine affinity column and tandem mass spectrometry. Anal. Biochem. 354, 279–89 (2006).

    Article  CAS  Google Scholar 

  31. Van Veldhoven, P. P., Gijsbers, S., Mannaerts, G. P., Vermeesch, J. R. & Brys, V. Human sphingosine-1-phosphate lyase: cDNA cloning, functional expression studies and mapping to chromosome 10q22(1). Biochim. Biophys. Acta 1487, 128–34 (2000).

    Article  Google Scholar 

  32. Bourquin, F., Riezman, H., Capitani, G. & Grutter, M. G. Structure and function of sphingosine-1-phosphate lyase, a key enzyme of sphingolipid metabolism. Structure 18, 1054–65 (2010).

    Article  CAS  Google Scholar 

  33. Suh, J. H. & Saba, J. D. Sphingosine-1-phosphate in inflammatory bowel disease and colitis-associated colon cancer: the fat’s in the fire. Transl. Cancer Res. 4, 469–83 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Miller, R. L., Garfinkel, R., Lendor, C., Hoepner, L., Li, Z. & Romanoff, L. et al. Polycyclic aromatic hydrocarbon metabolite levels and pediatric allergy and asthma in an inner-city cohort. Pediatr. Allergy Immunol. 21, 260–7 (2010).

    Article  Google Scholar 

  35. Olivera, A., Urtz, N., Mizugishi, K., Yamashita, Y., Gilfillan, A. M. & Furumoto, Y. et al. IgE-dependent activation of sphingosine kinases 1 and 2 and secretion of sphingosine 1-phosphate requires Fyn kinase and contributes to mast cell responses. J. Biol. Chem. 281, 2515–25 (2006).

    Article  CAS  Google Scholar 

  36. Huang, S. K., Zhang, Q., Qiu, Z. & Chung, K. F. Mechanistic impact of outdoor air pollution on asthma and allergic diseases. J. Thorac. Dis. 7, 23–33 (2015).

    PubMed  PubMed Central  Google Scholar 

  37. Stanek, L. W., Brown, J. S., Stanek, J., Gift, J. & Costa, D. L. Air pollution toxicology—a brief review of the role of the science in shaping the current understanding of air pollution health risks. Toxicol. Sci. 120, S8–27 (2011).

    Article  CAS  Google Scholar 

  38. Klingbeil, E. C., Hew, K. M., Nygaard, U. C. & Nadeau, K. C. Polycyclic aromatic hydrocarbons, tobacco smoke, and epigenetic remodeling in asthma. Immunol. Res. 58, 369–73 (2014).

    Article  CAS  Google Scholar 

  39. Rosa, M. J., Jung, K. H., Perzanowski, M. S., Kelvin, E. A., Darling, K. W. & Camann, D. E. et al. Prenatal exposure to polycyclic aromatic hydrocarbons, environmental tobacco smoke and asthma. Respir. Med. 105, 869–76 (2011).

    Article  Google Scholar 

  40. Flory, J. H., Sleiman, P. M., Christie, J. D., Annaiah, K., Bradfield, J. & Kim, C. E. et al. 17q12-21 variants interact with smoke exposure as a risk factor for pediatric asthma but are equally associated with early-onset versus late-onset asthma in North Americans of European ancestry. J. Allergy Clin. Immunol. 124, 605–7 (2009).

    Article  CAS  Google Scholar 

  41. Jolly, P. S., Rosenfeldt, H. M., Milstien, S. & Spiegel, S. The roles of sphingosine-1-phosphate in asthma. Mol. Immunol. 38, 1239–45 (2002).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported, in part, by grants from the National Health Research Institutes, Taiwan (EOPP10-014 and EOSP07-014 to S.-K.H.), Kaohsiung Medical University “The Talent Plan” (105KMUOR04 to S.-K.H.), the Ministry of Science and Technology, Taiwan (MOST 105-2320-B-039-004 and MOST 106-2320-B-039-037, to H.-C.W.), China Medical University Hospital, Taiwan (DMR-106-154 and DMR-107-117, to H.-C.W.), the Community Medicine Research Center, Chang Gung Memorial Hospital at Keelung (CMRPG3E1183 to L.-C.C.), the 1000 Young Talents Plan Program, China (to Y.Z.), the Initial Funding for New PI, Fudan Children’s Hospital and Fudan University (to Y.Z.), the National Natural Science Foundation of China (81671561, to Y.Z.), and the National Key Research and Development Program of China (2016YFC1305102, to Y.Z.). We thank the Center for Research Resources and Development of Kaohsiung Medical University for providing the Olympus FV1000 confocal microscope.

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Authors and Affiliations

  1. Department of Medical Research, China Medical University Hospital, China Medical University, 40402, Taichung, Taiwan, China

    Hsueh-Chun Wang

  2. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, China

    Tzu-Hsuan Wong, Li-Ting Wang, Hsiang-Han Su, Jau-Ling Suen, Shih-Hsien Hsu & Shau-Ku Huang

  3. Division of Allergy, Asthma and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan, China

    Hsiu-Yueh Yu, Ai-Hsuan Wu & Li-Chen Chen

  4. National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan, China

    Yu-Chun Lin, Hua-Ling Chen & Shau-Ku Huang

  5. Research Center of Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, China

    Jau-Ling Suen, Shih-Hsien Hsu & Shau-Ku Huang

  6. Center for Research Resources and Development, Kaohsiung Medical University, Kaohsiung, Taiwan, China

    Jau-Ling Suen

  7. Community Medicine Research Center, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan, China

    Li-Chen Chen

  8. Department of Pediatrics, Xiamen Chang Gung Hospital, Xiamen, China

    Li-Chen Chen

  9. Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Yufeng Zhou & Shau-Ku Huang

  10. Key Laboratory of Neonatal Disease, Children’s Hospital and Institute of Biomedical Sciences, Ministry of Health, Fudan University, 201102, Shanghai, China

    Yufeng Zhou

  11. Lou-Hu Hospital, Shen-Zhen University, Shen-Zhen, China

    Shau-Ku Huang

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Wang, HC., Wong, TH., Wang, LT. et al. Aryl hydrocarbon receptor signaling promotes ORMDL3-dependent generation of sphingosine-1-phosphate by inhibiting sphingosine-1-phosphate lyase. Cell Mol Immunol 16, 783–790 (2019). https://doi.org/10.1038/s41423-018-0022-2

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