title: SP-R210 (Myo18A) Isoforms as Intrinsic Modulators of Macrophage Priming and Activation.
abstract: The surfactant protein (SP-A) receptor SP-R210 has been shown to increase phagocytosis of SP-A-bound pathogens and to modulate cytokine secretion by immune cells. SP-A plays an important role in pulmonary immunity by enhancing opsonization and clearance of pathogens and by modulating macrophage inflammatory responses. Alternative splicing of the Myo18A gene results in two isoforms: SP-R210S and SP-R210L, with the latter predominantly expressed in alveolar macrophages. In this study we show that SP-A is required for optimal expression of SP-R210L on alveolar macrophages. Interestingly, pre-treatment with SP-A prepared by different methods either enhances or suppresses responsiveness to LPS, possibly due to differential co-isolation of SP-B or other proteins. We also report that dominant negative disruption of SP-R210L augments expression of receptors including SR-A, CD14, and CD36, and enhances macrophages' inflammatory response to TLR stimulation. Finally, because SP-A is known to modulate CD14, we used a variety of techniques to investigate how SP-R210 mediates the effect of SP-A on CD14. These studies revealed a novel physical association between SP-R210S, CD14, and SR-A leading to an enhanced response to LPS, and found that SP-R210L and SP-R210S regulate internalization of CD14 via distinct macropinocytosis-like mechanisms. Together, our findings support a model in which SP-R210 isoforms differentially regulate trafficking, expression, and activation of innate immune receptors on macrophages.
authors.affiliation: Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America; Pulmonary Immunology and Physiology Laboratory, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Linlin
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America; Pulmonary Immunology and Physiology Laboratory, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Marykate
authors.initials: M
authors.lastname: Carrillo
authors.affiliation: Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America; Pulmonary Immunology and Physiology Laboratory, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Yuchieh M
authors.initials: YM
authors.lastname: Wu
authors.affiliation: Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America; Center of Host Defense and Lung Disease Research, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Susan L
authors.initials: SL
authors.lastname: DiAngelo
authors.affiliation: Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America; Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America; Center of Host Defense and Lung Disease Research, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America; Pulmonary Immunology and Physiology Laboratory, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Patricia
authors.initials: P
authors.lastname: Silveyra
authors.affiliation: Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America; Center of Host Defense and Lung Disease Research, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Umstead
authors.affiliation: Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America; Division of Pediatric Critical Care Penn State Hershey Children's Hospital, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America; Pulmonary Immunology and Physiology Laboratory, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: E Scott
authors.initials: ES
authors.lastname: Halstead
authors.affiliation: Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America; Pulmonary Immunology and Physiology Laboratory, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Davies
authors.affiliation: Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America; Pulmonary Immunology and Physiology Laboratory, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Sanmei
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America; Department of Obstetrics and Gynecology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America; Center of Host Defense and Lung Disease Research, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Joanna
authors.initials: J
authors.lastname: Floros
authors.affiliation: Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
authors.forename: Francis X
authors.initials: FX
authors.lastname: McCormack
authors.affiliation: Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America; Department of Pathology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America; The Jake Gittlen Laboratories for Cancer Research, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Neil D
authors.initials: ND
authors.lastname: Christensen
authors.affiliation: Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America; Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America; Pulmonary Immunology and Physiology Laboratory, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America.
authors.forename: Zissis C
authors.initials: ZC
authors.lastname: Chroneos
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology; D018950:Lipopolysaccharide Receptors / Q000235:genetics* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism; D009218:Myosins / Q000235:genetics* / Q000378:metabolism; D010587:Phagocytosis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D037662:Pulmonary Surfactant-Associated Protein A / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; C407101:Myo18a protein, mouse; D020033:Protein Isoforms; D037662:Pulmonary Surfactant-Associated Protein A; D009218:Myosins