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SP-R210 (Myo18A) Isoforms as Intrinsic Modulators of Macrophage Priming and Activation
Linlin Yang1, Marykate Carrillo1, Yuchieh M Wu1
1Department 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.
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.
Insights
Surfactant protein (SP-A) regulates SP-R210 expression on macrophages, impacting innate immune responses. SP-R210 isoforms control receptor trafficking and activation, influencing pulmonary immunity.
Area of Science:
- Immunology
- Cell Biology
- Pulmonary Medicine
Background:
- Surfactant protein A (SP-A) is crucial for pulmonary immunity, enhancing pathogen clearance and modulating macrophage responses.
- SP-A receptor SP-R210, derived from the Myo18A gene, exists as SP-R210S and SP-R210L isoforms, with SP-R210L dominant in alveolar macrophages.
- SP-R210 influences pathogen phagocytosis and immune cell cytokine secretion.
Purpose of the Study:
- To investigate the role of SP-A in regulating SP-R210 expression on alveolar macrophages.
- To elucidate how SP-R210 isoforms mediate SP-A's effects on innate immune receptor expression and function.
- To understand the mechanisms by which SP-R210 regulates CD14 trafficking and macrophage inflammatory responses.
Main Methods:
- Investigated SP-A's requirement for SP-R210L expression on alveolar macrophages.
- Utilized dominant-negative disruption of SP-R210L to assess its impact on receptor expression (SR-A, CD14, CD36) and TLR-stimulated inflammatory responses.
- Employed various techniques to examine SP-R210's mediation of SP-A's effect on CD14, including co-immunoprecipitation and analysis of CD14 internalization mechanisms.
Main Results:
- SP-A is essential for optimal SP-R210L expression on alveolar macrophages.
- Disruption of SP-R210L increased SR-A, CD14, and CD36 expression and augmented macrophage inflammatory responses to TLR stimulation.
- A physical association between SP-R210S, CD14, and SR-A was identified, enhancing LPS response.
- SP-R210 isoforms regulate CD14 internalization via distinct macropinocytosis-like pathways.
Conclusions:
- SP-R210 isoforms play distinct roles in regulating the expression, trafficking, and activation of innate immune receptors on macrophages.
- These findings reveal a novel mechanism by which SP-A and SP-R210 coordinate innate immune responses in the lung.
- The study provides a framework for understanding how SP-R210 influences macrophage function in pulmonary immunity.
