A specific sphingosine kinase 1 inhibitor attenuates airway hyperresponsiveness and inflammation in a mast cell–dependent murine model of allergic asthma

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Presentation transcript:

A specific sphingosine kinase 1 inhibitor attenuates airway hyperresponsiveness and inflammation in a mast cell–dependent murine model of allergic asthma Megan M. Price, PhD, Carole A. Oskeritzian, PhD, Yves T. Falanga, BSc, Kuzhuvelil B. Harikumar, PhD, Jeremy C. Allegood, PhD, Sergio E. Alvarez, PhD, Daniel Conrad, PhD, John J. Ryan, PhD, Sheldon Milstien, PhD, Sarah Spiegel, PhD Journal of Allergy and Clinical Immunology Volume 131, Issue 2, Pages 501-511.e1 (February 2013) DOI: 10.1016/j.jaci.2012.07.014 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Inhibition of SphK1 reduces activation of human mast cells. IgE-sensitized skin-derived mast cells were treated without (open bars) or with (gray bars, 2.5 μmol/L; black bars, 5 μmol/L) SKI-1 and then stimulated with vehicle, 30 ng/mL antigen (IgE/Ag), 100 nmol/L S1P, or 1 μmol/L ionomycin (Iono). A and B, Degranulation was determined based on β-hexosaminidase release (Fig 1, A), and viability was determined by means of trypan blue exclusion after 24 hours (Fig 1, B). C-E, Secretion of TNF-α (Fig 1, C), IL-6 (Fig 1, D), and CCL2 (Fig 1, E) was measured by means of ELISA. Data are means ± SDs of triplicate determinations. *P < .01. Similar results were obtained by using cells from 2 different donors. Journal of Allergy and Clinical Immunology 2013 131, 501-511.e1DOI: (10.1016/j.jaci.2012.07.014) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Inhibition of SphK1 reduces murine mast cell activation. Sensitized BMMCs were treated without (open bars) or with (black bars, 10 μmol/L) SKI-1 and then stimulated with vehicle (PBS) or with 20 ng/mL antigen (IgE/Ag). A and B, Secretion of histamine was measured by means of ELISA (Fig 2, A), and viability was determined by using trypan blue exclusion after 24 hours (Fig 2, B). C-F, Secretion of TNF-α (Fig 2, C), IL-6 (Fig 2, D), IL-13 (Fig 2, E), and macrophage inflammatory protein 1α (MIP-1α; Fig 2, F) was measured by using ELISA. Data are means ± SDs of triplicate determinations. *P < .01. G, IgE-sensitized BMMCs were treated without or with antigen for 5 minutes, and cell lysates were immunoblotted with antibodies against phosphorylated IκBα, IKK, and extracellular signal–regulated kinase (ERK) 1/2 and total ERK2 as a loading control. Journal of Allergy and Clinical Immunology 2013 131, 501-511.e1DOI: (10.1016/j.jaci.2012.07.014) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Effect of SK1-I on development of OVA-induced mast cell–dependent AHR. A, Mast cell– and IgE-dependent allergic asthma model. Mice were sensitized and challenged with OVA administered intraperitoneally (50 μg) or intranasally (200 μg), respectively, on the indicated days. PBS or SK1-I (100 μg) was administered intranasally 1 hour before OVA sensitization and challenge (group 1) or only before the OVA challenge (group 2). Unsensitized mice received either PBS or SK1-I on days 1, 3, 5, 7, 22, 25, and 28. Airway responses to methacholine were measured with the flexiVent apparatus on day 29, 24 hours after the last intranasal OVA or PBS challenge. B-E, Lung resistance (RL; Fig 3, B), compliance (C; Fig 3, C), Newtonian resistance (RN; Fig 3, D), and tissue damping (TD; Fig 3, E). *P < .05 compared with OVA-challenged mice. Data are means ± SEMs from at least 7 mice in each group and are shown as fold changes. Journal of Allergy and Clinical Immunology 2013 131, 501-511.e1DOI: (10.1016/j.jaci.2012.07.014) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Inhibition of SphK1 attenuates airway immune cell infiltration and mucus secretion. Mice were sensitized, challenged, and treated as described in Fig 3. A and B, At day 29, lung sections were fixed and stained with hematoxylin and eosin (H&E; Fig 4, A; scale bar = 100 μm) or periodic acid/Alcian blue/Schiff (PAS; Fig 4, B) and photographed under light microscopy at ×100 magnification (scale bar = 50 μm). Prominent infiltrates of inflammatory cells are present in OVA-sensitized and OVA-challenged mice but not in SK1-I–treated mice. C, Peribronchial and perivascular inflammation were scored as described in the Methods section. D, Mucin levels in BAL fluid were measured by using a mucin-specific ELISA. E and F, Total (Fig 4, E) and degranulated (Fig 4, F) mast cells in lung sections were determined as described in the Methods section. Data are means ± SEMs. *P < .05 compared with OVA-challenged mice. Journal of Allergy and Clinical Immunology 2013 131, 501-511.e1DOI: (10.1016/j.jaci.2012.07.014) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 SK1-I treatment reduces airway eosinophilia. Mice were sensitized, challenged, and treated as described in Fig 3. BAL fluid was collected on day 29, and the numbers of eosinophils, neutrophils, macrophages, and lymphocytes were determined. *P < .05 compared with OVA-challenged mice. Data are means ± SEMs from at least 7 mice in each group. Journal of Allergy and Clinical Immunology 2013 131, 501-511.e1DOI: (10.1016/j.jaci.2012.07.014) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Effect of SK1-I on S1P levels in lungs and sera. Mice were sensitized, challenged, and treated as described in Fig 3. On day 29, lung tissue (A and B) and sera (C and D) were collected, and levels of S1P, dihydro-S1P (DHS1P), and SK1-I were determined by using liquid chromatography–electrospray ionization–tandem mass spectrometry. †P < .05 compared with PBS-treated mice. *P < .05 compared with OVA-challenged mice. Journal of Allergy and Clinical Immunology 2013 131, 501-511.e1DOI: (10.1016/j.jaci.2012.07.014) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Inhibition of SphK1 attenuates activation of NF-κB in the lungs of OVA-challenged mice. Mice were sensitized, challenged, and treated as described in Fig 3. A, At day 29, lung sections were fixed and stained with anti-p65 (phospho-Ser276) antibody and photographed under light microscopy at ×200 magnification. Scale bar = 50 μm. B, Lungs were homogenized, and equal amounts of proteins were analyzed by means of immunoblotting with anti-p65 (phospho-Ser536) antibody. Blots were stripped and blotted with p65 antibody to demonstrate equal loading and transfer. Journal of Allergy and Clinical Immunology 2013 131, 501-511.e1DOI: (10.1016/j.jaci.2012.07.014) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 8 SK1-I reduces OVA challenge–induced pulmonary cytokines and chemokines. Mice were sensitized, challenged, and treated as described in Fig 3. On day 29, BAL fluid was collected, and levels of the indicated cytokines and chemokines were measured by using the Bio-Plex assay. Data are means ± SEMs from at least 7 mice in each group. *P < .05 compared with OVA-challenged mice. †P < .05 compared with PBS-treated mice. Journal of Allergy and Clinical Immunology 2013 131, 501-511.e1DOI: (10.1016/j.jaci.2012.07.014) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Airway inflammation and hyperreactivity to methacholine are reduced in OVA-sensitized and OVA-challenged mast cell–deficient KitW-sh/W-sh mice. KitW-sh/W-sh and wild-type congenic mice were sensitized and challenged with OVA or PBS as described in Fig 3. Airway responses to methacholine were measured with the flexiVent apparatus 24 hours after the last intranasal OVA or PBS challenge. A, Lung resistances (RL) are shown as fold changes. B, Lung sections were fixed and stained with hematoxylin and eosin. Scale bar = 100 μm. Journal of Allergy and Clinical Immunology 2013 131, 501-511.e1DOI: (10.1016/j.jaci.2012.07.014) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions