Sphingosine-1-phosphate receptor 2 protects against anaphylactic shock through suppression of endothelial nitric oxide synthase in mice Hong Cui, MD,

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Sphingosine-1-phosphate receptor 2 protects against anaphylactic shock through suppression of endothelial nitric oxide synthase in mice Hong Cui, MD, PhD, Yasuo Okamoto, MD, PhD, Kazuaki Yoshioka, PhD, Wa Du, MD, PhD, Noriko Takuwa, MD, PhD, Wei Zhang, MD, PhD, Masahide Asano, PhD, Toshishige Shibamoto, MD, PhD, Yoh Takuwa, MD, PhD Journal of Allergy and Clinical Immunology Volume 132, Issue 5, Pages 1205-1214.e9 (November 2013) DOI: 10.1016/j.jaci.2013.07.026 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 S1pr2 deficiency exacerbates vascular leakage in active anaphylaxis. Mice that had been sensitized with BSA were challenged with intravenous (i.v.) injection of BSA. A and B, Evans blue leakage in lungs of mice 10 minutes after BSA challenge or saline infusion. Fig 1, A, Representative lung photographs. Fig 1, B, Quantification of Evans blue leakage in the lung. C, Hematocrit (HCT) levels 10 minutes after BSA challenge. D, Survival of BSA-challenged WT and S1pr2−/− mice. Numbers in parentheses denote numbers of mice or samples analyzed throughout the figures. **P < .01 and ***P < .001. If not marked, differences were not statistically significant. Journal of Allergy and Clinical Immunology 2013 132, 1205-1214.e9DOI: (10.1016/j.jaci.2013.07.026) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 S1pr2 deficiency augments PAF injection–induced phosphorylation of Akt and eNOS in aortas and lungs and production of cGMP in aortas. A-D, PAF-stimulated phosphorylation of Akt at Ser473 and eNOS at Ser1177 in aortas (Fig 2, A and B) and lungs (Fig 2, C and D) of WT and S1pr2−/− mice that were intravenously injected with saline or PAF. E, PAF injection–stimulated increase in cGMP levels in the aorta. cGMP was extracted, and levels were determined with an ELISA kit. *P < .05, **P < .01, and ***P < .001. If not marked, differences were not statistically significant. Journal of Allergy and Clinical Immunology 2013 132, 1205-1214.e9DOI: (10.1016/j.jaci.2013.07.026) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Genetic eNOS deficiency restores aggravation of vascular leakage after PAF injection and antigen challenge in S1pr2−/− mice. A, Hematocrit (HCT) levels 10 minutes after PAF injection in WT and S1pr2−/− mice with or without Nos3 deficiency. B, Survival after PAF injection of WT and S1pr2−/− mice with or without Nos3 deficiency. C, Hematocrit levels 10 minutes after BSA challenge in S1pr2+/+ and S1pr2−/− mice with or without Nos3 deficiency. D, Changes in mean arterial blood pressure after BSA challenge in S1pr2+/+ and S1pr2−/− mice with or without Nos3 deficiency. E, Survival after BSA challenge of S1pr2+/+ and S1pr2−/− mice with or without Nos3 deficiency. i.v., Intravenous. *P < .05, **P < .01, and ***P < .001. If not marked, differences were not statistically significant. Journal of Allergy and Clinical Immunology 2013 132, 1205-1214.e9DOI: (10.1016/j.jaci.2013.07.026) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 PAF- and S1P-stimulated phosphorylation of Akt and eNOS and production of NO are exaggerated in S1pr2-deficient ECs. A and B, PAF (100 nmol/L)– and S1P (100 nmol/L)–stimulated phosphorylation of Akt at Ser473 (Fig 4, A) and eNOS at Ser1177 (Fig 4, B) in MLECs isolated from WT and S1pr2−/− mice. Serum-starved MLECs were stimulated as indicated for 20 minutes. Top, Representative blots. Bottom, Quantified data. C, PAF (50 nmol/L)–, VEGF-A165 (10 ng/mL)–, and S1P (100 nmol/L)–stimulated increase in NO production in MLECs. NO released into media for 3 hours was identified as NO2− and NO3−. *P < .05, **P < .01, and ***P < .001. If not marked, differences were not statistically significant. Journal of Allergy and Clinical Immunology 2013 132, 1205-1214.e9DOI: (10.1016/j.jaci.2013.07.026) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 PAF-induced disruption of AJs is aggravated by S1pr2 deficiency and rescued by a NOS inhibitor in ECs. A, Immunofluorescent staining with anti–VE-cadherin (green) or anti–β-catenin antibody (red) in MLECs. MLECs were stimulated or not with PAF (100 nmol/L) for 30 minutes with or without L-NAME (1 mmol/L) in the presence of 1% FBS. Bars = 20 μm. B, PAF- and S1P-induced S-nitrosylation of β-catenin in MLECs. Serum-starved MLECs were pretreated or not with S1P (30 nmol/L) plus L-NAME (1 mmol/L) or S1P alone for 10 minutes and then stimulated with PAF (100 nmol/L) for 30 minutes, followed by analysis with the biotin-switch method and Western blotting with anti–β-catenin antibody. Left, Representative blots. Right, Quantified data of S-nitroso–β-catenin. *P < .05, **P < .01, and ****P < .001. If not marked, differences were not statistically significant. Journal of Allergy and Clinical Immunology 2013 132, 1205-1214.e9DOI: (10.1016/j.jaci.2013.07.026) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 S1pr2 deficiency exacerbates vascular leakage during active anaphylaxis. Mice that had been sensitized with OVA were challenged with intravenous injection of OVA. A and B, Evans blue leakage in lungs of mice 10 minutes after OVA challenge or saline infusion. Fig E1, A, Representative lung photographs. Fig E1, B, Quantification of Evans blue leakage in lungs. C, Hematocrit (HCT) levels 10 minutes after OVA challenge. Numbers in parentheses denote the numbers of mice or samples analyzed throughout the Online Repository figures. *P < .05, **P < .01, and ***P < .001. If not marked, differences were not statistically significant. Journal of Allergy and Clinical Immunology 2013 132, 1205-1214.e9DOI: (10.1016/j.jaci.2013.07.026) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 S1pr2 deficiency exacerbates PAF-induced vascular leakage. A and B, Evans blue leakage in lungs 10 minutes after injection of saline or PAF. Fig E2, A, Representative lung photographs. Fig E2, B, Quantification of Evans blue leakage in lung. C, Representative images of hematoxylin and eosin–stained lung sections. Bars = 100 μm. D, Hematocrit (HCT) levels 10 minutes after injection of saline or PAF. E, Survival of WT and S1pr2−/− mice receiving intravenous (i.v.) injection of PAF. F, Miles assay. Top, Representative skin photographs of WT and S1pr2−/− mice. Bottom, Quantification of Evans blue extravasation in the skin. *P < .05, **P < .01, and ***P < .001. If not marked, differences were not statistically significant. Journal of Allergy and Clinical Immunology 2013 132, 1205-1214.e9DOI: (10.1016/j.jaci.2013.07.026) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 S1pr2 deficiency exacerbates PAF-induced vascular leakage in mice that had been back-crossed with C57BL/6 mice. PAF-induced responses were analyzed in mice with LacZ knocked in at the S1pr2 locus that had been back-crossed with C57BL/6 mice 4 times. A and B, Evans blue leakage in the lungs 10 minutes after injection of saline or PAF. Fig E3, A, Representative lung photographs. Fig E3, B, Quantification of Evans blue leakage in lungs. C, Hematocrit (HCT) levels 10 minutes after PAF injection. *P < .05 and ***P < .001. Journal of Allergy and Clinical Immunology 2013 132, 1205-1214.e9DOI: (10.1016/j.jaci.2013.07.026) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 S1pr2 deficiency exacerbates vascular leakage and impairs survival after PAF injection in nonanesthetized mice. A, Hematocrit (HCT) levels 10 minutes after injection of saline or PAF. B, Survival of WT and S1pr2−/− mice receiving intravenous (i.v.) injection of PAF. *P < .05 and ***P < .001. If not marked, differences were not statistically significant. Journal of Allergy and Clinical Immunology 2013 132, 1205-1214.e9DOI: (10.1016/j.jaci.2013.07.026) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Pharmacologic NO synthase inhibition restores aggravation of PAF-induced vascular leakage in S1P2-deficient mice. A, Hematocrit (HCT) levels 10 minutes after injection of saline or PAF in WT and S1pr2−/− mice with or without L-NAME administration. B, Survival after PAF injection of WT and S1pr2−/− mice with or without L-NAME pretreatment. i.v., Intravenous. ***P < .001. If not marked, differences were not statistically significant. Journal of Allergy and Clinical Immunology 2013 132, 1205-1214.e9DOI: (10.1016/j.jaci.2013.07.026) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 Genetic eNOS deficiency restores aggravation of hypothermia in active anaphylaxis in S1pr2−/− mice. A, Plasma level of histamine in S1pr2+/+ and S1pr2−/− mice with or without Nos3 deficiency after injection of BSA or saline. B, Changes in body temperature after BSA challenge in S1pr2+/+ and S1pr2−/− mice with or without Nos3 deficiency. i.v., Intravenous. *P < .05, **P < .01, and ***P < .001. If not marked, differences were not statistically significant. Journal of Allergy and Clinical Immunology 2013 132, 1205-1214.e9DOI: (10.1016/j.jaci.2013.07.026) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions