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

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 infl...

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Bibliographic Details
Published in:PloS one 2015-05, Vol.10 (5), p.e0126576
Main Authors: Yang, Linlin, Carrillo, Marykate, Wu, Yuchieh M, DiAngelo, Susan L, Silveyra, Patricia, Umstead, Todd M, Halstead, E Scott, Davies, Michael L, Hu, Sanmei, Floros, Joanna, McCormack, Francis X, Christensen, Neil D, Chroneos, Zissis C
Format: Article
Language:English
Subjects:
Alternative splicing
Alternative Splicing - genetics
Alveoli
Biochemistry
CD14 antigen
CD36 antigen
Cell activation
Critical care
Cytokines
Humans
Immune clearance
Immune system
Immunity
Immunity, Innate - genetics
Immunology
Inflammation
Inflammation - chemically induced
Inflammation - genetics
Inflammation - immunology
Inflammatory response
Internalization
Isoforms
Kinases
Laboratories
Lipids
Lipopolysaccharide Receptors - genetics
Lipopolysaccharide Receptors - metabolism
Lipopolysaccharides
Lipopolysaccharides - toxicity
Lung diseases
Macrophages
Macrophages, Alveolar - immunology
Macrophages, Alveolar - metabolism
Medical research
Medicine
Modulators
Myosins - genetics
Myosins - metabolism
Opsonization
Pathogens
Pediatrics
Phagocytosis
Physicians
Physiology
Priming
Protein Isoforms - genetics
Protein Isoforms - metabolism
Proteins
Pulmonary Surfactant-Associated Protein A - administration & dosage
Pulmonary Surfactant-Associated Protein A - metabolism
Receptors
Surfactant protein A
Surfactants
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0126576