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Sphingomyelin Synthase 2 and Caveolin 1 Mediate TLR4 and ER Stress Responses
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A6369 - Sphingomyelin Synthase 2 and Caveolin 1 Mediate TLR4 and ER Stress Responses
Author Block: P. Geraghty1, J. Poon1, M. White2, A. Dabo1, N. G. McElvaney2, E. P. Reeves2, R. Wadgaonkar1; 1SUNY Downstate Medical Center, New York, NY, United States, 2Royal College of Surgeons in Ireland, Dublin, Ireland.
Introduction/rationale to the study: Altered immune responses and endoplasmic reticulum (ER) stress are frequently linked to the progression of several pulmonary diseases. Lipid raft microdomains are small lipid-enriched pockets in the plasma membrane that are important sites for receptor clustering and signaling. Loss of expression of two lipid raft-associated proteins, sphingomyelin synthase 2 (SMS2) and caveolin 1 (Cav1), suppresses TLR4-mediated responses. TLR4 signaling subdues the ER unfolded protein response (UPR). Therefore, we examine whether SMS2 and Cav1 interact with TLR4 in lipid rafts to influence lipopolysaccharides (LPS) responses and investigate the subsequent impact on ER stress. Methods used: Lipid rafts were isolated from SMS2 expressing and non-expressing human pulmonary artery endothelial cells following LPS stimuli. SMS2, Cav1 and TLR4 localization was examined. Cav1 knockout (-/-) mice were administered LPS intranasally and immune responses and ER stress markers were quantified. ER stress was induced in Cav1-/- macrophages with tunicamycin and immune responses and ER stress markers were examined. Results of the study: SMS2 and TLR4 co-localized in Cav1 rich lipid raft fractions during LPS treatment. Loss of SMS2 expression results in failure of TLR4 translocation to these fractions during LPS treatment. This coincides with reduced immune responses to LPS and enhanced ER stress. Cav1-/- mice have reduced lung immune cell infiltration, cytokine production and enhanced ER stress following LPS administration to the airways. Similarly, tunicamycin treated Cav1-/- macrophages have heighted ER stress and reduced inflammation compared to wild type control macrophages. Conclusions of the study: The SMS2-Cav1 interaction is an important mediator of TLR4 responses, which has a direct effect on immune responses and ER stress outcomes in the lung.
Author Block: P. Geraghty1, J. Poon1, M. White2, A. Dabo1, N. G. McElvaney2, E. P. Reeves2, R. Wadgaonkar1; 1SUNY Downstate Medical Center, New York, NY, United States, 2Royal College of Surgeons in Ireland, Dublin, Ireland.
Introduction/rationale to the study: Altered immune responses and endoplasmic reticulum (ER) stress are frequently linked to the progression of several pulmonary diseases. Lipid raft microdomains are small lipid-enriched pockets in the plasma membrane that are important sites for receptor clustering and signaling. Loss of expression of two lipid raft-associated proteins, sphingomyelin synthase 2 (SMS2) and caveolin 1 (Cav1), suppresses TLR4-mediated responses. TLR4 signaling subdues the ER unfolded protein response (UPR). Therefore, we examine whether SMS2 and Cav1 interact with TLR4 in lipid rafts to influence lipopolysaccharides (LPS) responses and investigate the subsequent impact on ER stress. Methods used: Lipid rafts were isolated from SMS2 expressing and non-expressing human pulmonary artery endothelial cells following LPS stimuli. SMS2, Cav1 and TLR4 localization was examined. Cav1 knockout (-/-) mice were administered LPS intranasally and immune responses and ER stress markers were quantified. ER stress was induced in Cav1-/- macrophages with tunicamycin and immune responses and ER stress markers were examined. Results of the study: SMS2 and TLR4 co-localized in Cav1 rich lipid raft fractions during LPS treatment. Loss of SMS2 expression results in failure of TLR4 translocation to these fractions during LPS treatment. This coincides with reduced immune responses to LPS and enhanced ER stress. Cav1-/- mice have reduced lung immune cell infiltration, cytokine production and enhanced ER stress following LPS administration to the airways. Similarly, tunicamycin treated Cav1-/- macrophages have heighted ER stress and reduced inflammation compared to wild type control macrophages. Conclusions of the study: The SMS2-Cav1 interaction is an important mediator of TLR4 responses, which has a direct effect on immune responses and ER stress outcomes in the lung.
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