title: The p110δ subunit of PI3K regulates bone marrow-derived eosinophil trafficking and airway eosinophilia in allergen-challenged mice.
abstract: Trafficking and recruitment of eosinophils during allergic airway inflammation is mediated by the phosphatidylinositol 3-kinase (PI3K) family of signaling molecules. The role played by the p110δ subunit of PI3K (PI3K p110δ) in regulating eosinophil trafficking and recruitment was investigated using a selective pharmacological inhibitor (IC87114). Treatment with the PI3K p110δ inhibitor significantly reduced murine bone marrow-derived eosinophil (BM-Eos) adhesion to VCAM-1 as well as ICAM-1 and inhibited activation-induced changes in cell morphology associated with reduced Mac-1 expression and aberrant cell surface localization/distribution of Mac-1 and α4. Infused BM-Eos demonstrated significantly decreased rolling and adhesion in inflamed cremaster muscle microvessels of mice treated with IC87114 compared with vehicle-treated mice. Furthermore, inhibition of PI3K p110δ significantly attenuated eotaxin-1-induced BM-Eos migration and prevented eotaxin-1-induced changes in the cytoskeleton and cell morphology. Knockdown of PI3K p110δ with siRNA in BM-Eos resulted in reduced rolling, adhesion, and migration, as well as inhibition of activation-induced changes in cell morphology, validating its role in regulating trafficking and migration. Finally, in a mouse model of cockroach antigen-induced allergic airway inflammation, oral administration of the PI3K p110δ inhibitor significantly inhibited airway eosinophil recruitment, resulting in attenuation of airway hyperresponsiveness in response to methacholine, reduced mucus secretion, and expression of proinflammatory molecules (found in inflammatory zone-1 and intelectin-1). Overall, these findings indicate the important role played by PI3K p110δ in mediating BM-Eos trafficking and migration by regulating adhesion molecule expression and localization/distribution as well as promoting changes in cell morphology that favor recruitment during inflammation.
authors.affiliation: Laboratory of Allergic Diseases and Inflammation, Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, 55108, USA.
authors.forename: Bit Na
authors.initials: BN
authors.lastname: Kang
authors.forename: Sung Gil
authors.initials: SG
authors.lastname: Ha
authors.forename: Xiao Na
authors.initials: XN
authors.lastname: Ge
authors.forename: M
authors.initials: M
authors.lastname: Reza Hosseinkhani
authors.forename: Nooshin S
authors.initials: NS
authors.lastname: Bahaie
authors.forename: Yana
authors.initials: Y
authors.lastname: Greenberg
authors.forename: Malcolm N
authors.initials: MN
authors.lastname: Blumenthal
authors.forename: Kamal D
authors.initials: KD
authors.lastname: Puri
authors.forename: Savita P
authors.initials: SP
authors.lastname: Rao
authors.forename: P
authors.initials: P
authors.lastname: Sriramarao
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000378:metabolism; D001854:Bone Marrow Cells; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D054413:Chemokine CCL11 / Q000378:metabolism; D058534:Class I Phosphatidylinositol 3-Kinases; D004802:Eosinophilia / Q000276:immunology* / Q000378:metabolism; D004804:Eosinophils / Q000276:immunology* / Q000378:metabolism; D006967:Hypersensitivity / Q000276:immunology / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000096:biosynthesis; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D012137:Respiratory System / Q000276:immunology* / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism
chemical_list: D000225:Adenine; D054413:Chemokine CCL11; D058534:Class I Phosphatidylinositol 3-Kinases; D018799:Intercellular Adhesion Molecule-1; D016177:Macrophage-1 Antigen; D016210:Methacholine Chloride; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines; D034741:RNA, Small Interfering; D019010:Vascular Cell Adhesion Molecule-1; C477872:IC 87114; C421683:Pik3cd protein, mouse