Dysregulated synthesis of protectin D1 in eosinophils from patients with severe asthma Jun Miyata, MD, Koichi Fukunaga, MD, PhD, Ryo Iwamoto, MS, Yosuke.

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Dysregulated synthesis of protectin D1 in eosinophils from patients with severe asthma Jun Miyata, MD, Koichi Fukunaga, MD, PhD, Ryo Iwamoto, MS, Yosuke Isobe, MS, Kyoko Niimi, MD, Rina Takamiya, PhD, Takahisa Takihara, MD, Katsuyoshi Tomomatsu, MD, Yusuke Suzuki, MD, Tsuyoshi Oguma, MD, Koichi Sayama, MD, Hiroyuki Arai, PhD, Tomoko Betsuyaku, MD, PhD, Makoto Arita, PhD, Koichiro Asano, MD Journal of Allergy and Clinical Immunology Volume 131, Issue 2, Pages 353-360.e2 (February 2013) DOI: 10.1016/j.jaci.2012.07.048 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Lipidomic analysis of eicosanoids (A) and docosanoids (B) biosynthesized by activated eosinophils. Peripheral blood eosinophils purified from healthy subjects were stimulated with 2 μmol/L Ca2+ ionophore in the presence (open bars) or absence (solid bars) of 10 μmol/L DHA. The results are means ± SEMs of 3 experiments. *P < .05 compared with unstimulated cells. #P < .05 compared with the levels in the absence of DHA. Journal of Allergy and Clinical Immunology 2013 131, 353-360.e2DOI: (10.1016/j.jaci.2012.07.048) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 A, PD1 biosynthesis in polymorphonuclear leukocytes (PMN; open bars) and eosinophils (EOS; solid bars) isolated from peripheral blood of healthy subjects stimulated with 2 μmol/L A23187, 10 μmol/L DHA, or both. The results are means ± SEMs of 3 experiments. ND, Not detected. *P < .05 compared with vehicle-treated cells. #P < .05 compared with PMNs. B, PD1 biosynthesis in eosinophils in the presence or absence of 1 to 10 μmol/L DHA. The results are means ± SEMs of 3 experiments. *P < .01 versus the nonstimulated cells. Journal of Allergy and Clinical Immunology 2013 131, 353-360.e2DOI: (10.1016/j.jaci.2012.07.048) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Gene expression of major synthetic enzymes for lipid mediators in eosinophils (EOS; solid bars) and neutrophils (NEU; open bars) isolated from healthy subjects. The results are means ± SEMs of 3 or 4 experiments. *P < .05 and **P < .01 versus the levels in neutrophils. ALOX5, 5-Lipoxygenase; ALOX5AP, 5-lipoxygenase–associated protein; ALOX15, 15-lipoxygenase-1; ALOX15B, 15-lipoxygenase-2; LTA4H, LTA4 hydrolase; LTC4S, LTC4 synthase; PGHS2, PGH synthase-2. Journal of Allergy and Clinical Immunology 2013 131, 353-360.e2DOI: (10.1016/j.jaci.2012.07.048) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Effects of PD1 on the chemotaxis of eosinophils. Eosinophils were pretreated with PD1, and the chemotaxis to 5-oxo-ETE (100 nmol/L, A) or CCL11 (10 nmol/L, B) was examined. Chemotactic activity (percentage migration) is expressed as the ratio of eosinophil peroxidase activity in the migrated cells to the activity in the total loaded cells. The results are means ± SEMs of 4 to 5 experiments. *P < .05 compared with cells stimulated in the absence of PD1. Journal of Allergy and Clinical Immunology 2013 131, 353-360.e2DOI: (10.1016/j.jaci.2012.07.048) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Modulation of the expression of CD11b and CD62L (L-selectin) shedding in eosinophils by PD1. The levels of CD11b and L-selectin expression were measured in eosinophils cultured in the presence or absence of 100 nmol/L 5-oxo-ETE (A and B) and 100 nmol/L CCL11(C and D). *P < .05 and **P < .01 versus vehicle-treated cells (n = 4-5). Journal of Allergy and Clinical Immunology 2013 131, 353-360.e2DOI: (10.1016/j.jaci.2012.07.048) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Effects of PD1 on the production of O2− (A) and degranulation (B) of eosinophils stimulated with 1 μmol/L PAF in the presence or absence of 100 nmol/L 5-oxo-ETE and apoptosis/survival (C). The O2− production and degranulation was measured as the SOD-inhibitable decrease in cytochrome C (Cyt C) levels and the release of eosinophil-derived neurotoxin, respectively. Eosinophil apoptosis and IL-5–dependent survival was evaluated with flow cytometric analysis. The results are means ± SEMs of 3 to 5 experiments. Journal of Allergy and Clinical Immunology 2013 131, 353-360.e2DOI: (10.1016/j.jaci.2012.07.048) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 A, Amounts of 15-lipoxygenase mediators (PD1 and 15-HETE) and 5-lipoxygenase metabolites (5-HETE and 4-hydroxy DHA) released from eosinophils derived from healthy subjects (HS; n = 4) or patients with severe asthma (SA; n = 4). *P < .01 compared with healthy subjects. B, Gene expression of 15-lipoxygenase (ALOX15), leukotriene C4 synthase (LTC4S), 5-lipoxygenase (ALOX5), and 5-lipoxygenaseassociated protein (ALOX5AP) in eosinophils. Journal of Allergy and Clinical Immunology 2013 131, 353-360.e2DOI: (10.1016/j.jaci.2012.07.048) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 8 Hypothetical self-regulatory mechanism by lipid mediators of human neutrophils (NEU; top) and eosinophils (EOS; bottom). LTB4 and LTC4 produced by neutrophils, eosinophils, or both activate these cells through BLT1 and cysteinyl leukotriene 1/2 receptors. In contrast, LXA4 biosynthesized in the presence of neutrophils and epithelial cells that express 15-lipoxygenase inhibits the neutrophil functions through its receptor, ALX. In eosinophils a similar self-regulatory mechanism is mediated by PD1 and its unknown receptor in the presence of DHA. Journal of Allergy and Clinical Immunology 2013 131, 353-360.e2DOI: (10.1016/j.jaci.2012.07.048) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Lipid mediator biosynthesis in human eosinophils stimulated at 37°C for 60 minutes with 1 μmol/L PAF, 10 nmol/L CCL11, 10 ng/mL IL-5, or their combination. The levels of PD1 (in the presence of 10 μmol/L DHA) and 15-HETE were measured by using the LC-MS/MS method, and the levels of LTC4 and thromboxane B2 (TxB2) were measured by using ELISA. The results are means ± SEMs of 3 to 8 experiments. *P < .05 compared with unstimulated cells. Journal of Allergy and Clinical Immunology 2013 131, 353-360.e2DOI: (10.1016/j.jaci.2012.07.048) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions