2. Academic Validation
  3. SP-R210 (Myo18A) Isoforms as Intrinsic Modulators of Macrophage Priming and Activation

SP-R210 (Myo18A) Isoforms as Intrinsic Modulators of Macrophage Priming and Activation

  • PLoS One. 2015 May 12;10(5):e0126576. doi: 10.1371/journal.pone.0126576.
Linlin Yang 1,  Marykate Carrillo 1,  Yuchieh M Wu 1,  Susan L DiAngelo 2,  Patricia Silveyra 3,  Todd M Umstead 2,  E Scott Halstead 4,  Michael L Davies 1,  Sanmei Hu 1,  Joanna Floros 5,  Francis X McCormack 6,  Neil D Christensen 7,  Zissis C Chroneos 8
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 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.
  • 4 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.
  • 5 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.
  • 6 Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
  • 7 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.
  • 8 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.
PMID: 25965346 DOI: 10.1371/journal.pone.0126576
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.

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