Scavenger receptor class a plays a central role in mediating mortality and the development of the pro-inflammatory phenotype in polymicrobial sepsis.
Sepsis is a frequent complication in critical illness. The mechanisms that are involved in initiation and propagation of the disease are not well understood. Scavenger receptor A (SRA) is a membrane receptor that binds multiple polyanions such as oxidized LDL and endotoxin. Recent studies suggest th...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS Pathogens |
| Online Access: | http://europepmc.org/articles/PMC3469655?pdf=render |
| _version_ | 1818022763055546368 |
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| author | Tammy R Ozment Tuanzhu Ha Kevin F Breuel Tiffany R Ford Donald A Ferguson John Kalbfleisch John B Schweitzer Jim L Kelley Chuanfu Li David L Williams |
| author_facet | Tammy R Ozment Tuanzhu Ha Kevin F Breuel Tiffany R Ford Donald A Ferguson John Kalbfleisch John B Schweitzer Jim L Kelley Chuanfu Li David L Williams |
| author_sort | Tammy R Ozment |
| collection | DOAJ |
| description | Sepsis is a frequent complication in critical illness. The mechanisms that are involved in initiation and propagation of the disease are not well understood. Scavenger receptor A (SRA) is a membrane receptor that binds multiple polyanions such as oxidized LDL and endotoxin. Recent studies suggest that SRA acts as a pattern recognition receptor in the innate immune response. The goal of the present study was to determine the role of SRA in polymicrobial sepsis. SRA deficient (SRA(-/-)) and C57BL/6JB/6J (WT) male mice were subjected to cecal ligation and puncture (CLP) to induce polymicrobial sepsis. NFκB activity, myeloperoxidase activity, and co-association of SRA with toll like receptor (TLR) 4 and TLR2 was analyzed in the lungs. Spleens were analyzed for apoptosis. Serum cytokines and chemokines were assayed. Blood and peritoneal fluid were cultured for aerobic and anaerobic bacterial burdens. Long-term survival was significantly increased in SRA(-/-) septic mice (53.6% vs. 3.6%, p < 0.05) when compared to WT mice. NFκB activity was 45.5% lower in the lungs of SRA(-/-) septic mice versus WT septic mice (p < 0.05). Serum levels of interleukin (IL)-5, IL-6, IL-10 and monocyte chemoattractant protein -1 were significantly lower in septic SRA(-/-) mice when compared to septic WT mice (p < 0.05). We found that SRA immuno-precipitated with TLR4, but not TLR2, in the lungs of WT septic mice. We also found that septic SRA(-/-) mice had lower bacterial burdens than WT septic mice. SRA deficiency had no effect on pulmonary neutrophil infiltration or splenocyte apoptosis during sepsis. We conclude that SRA plays a pivotal, and previously unknown, role in mediating the pathophysiology of sepsis/septic shock in a murine model of polymicrobial sepsis. Mechanistically, SRA interacts with TLR4 to enhance the development of the pro-inflammatory phenotype and mediate the morbidity and mortality of sepsis/septic shock. |
| first_indexed | 2024-12-10T03:33:35Z |
| format | Article |
| id | doaj.art-492a3556ce7e4235a58346b1ff4341da |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-10T03:33:35Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Pathogens |
| spelling | doaj.art-492a3556ce7e4235a58346b1ff4341da2022-12-22T02:03:45ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742012-01-01810e100296710.1371/journal.ppat.1002967Scavenger receptor class a plays a central role in mediating mortality and the development of the pro-inflammatory phenotype in polymicrobial sepsis.Tammy R OzmentTuanzhu HaKevin F BreuelTiffany R FordDonald A FergusonJohn KalbfleischJohn B SchweitzerJim L KelleyChuanfu LiDavid L WilliamsSepsis is a frequent complication in critical illness. The mechanisms that are involved in initiation and propagation of the disease are not well understood. Scavenger receptor A (SRA) is a membrane receptor that binds multiple polyanions such as oxidized LDL and endotoxin. Recent studies suggest that SRA acts as a pattern recognition receptor in the innate immune response. The goal of the present study was to determine the role of SRA in polymicrobial sepsis. SRA deficient (SRA(-/-)) and C57BL/6JB/6J (WT) male mice were subjected to cecal ligation and puncture (CLP) to induce polymicrobial sepsis. NFκB activity, myeloperoxidase activity, and co-association of SRA with toll like receptor (TLR) 4 and TLR2 was analyzed in the lungs. Spleens were analyzed for apoptosis. Serum cytokines and chemokines were assayed. Blood and peritoneal fluid were cultured for aerobic and anaerobic bacterial burdens. Long-term survival was significantly increased in SRA(-/-) septic mice (53.6% vs. 3.6%, p < 0.05) when compared to WT mice. NFκB activity was 45.5% lower in the lungs of SRA(-/-) septic mice versus WT septic mice (p < 0.05). Serum levels of interleukin (IL)-5, IL-6, IL-10 and monocyte chemoattractant protein -1 were significantly lower in septic SRA(-/-) mice when compared to septic WT mice (p < 0.05). We found that SRA immuno-precipitated with TLR4, but not TLR2, in the lungs of WT septic mice. We also found that septic SRA(-/-) mice had lower bacterial burdens than WT septic mice. SRA deficiency had no effect on pulmonary neutrophil infiltration or splenocyte apoptosis during sepsis. We conclude that SRA plays a pivotal, and previously unknown, role in mediating the pathophysiology of sepsis/septic shock in a murine model of polymicrobial sepsis. Mechanistically, SRA interacts with TLR4 to enhance the development of the pro-inflammatory phenotype and mediate the morbidity and mortality of sepsis/septic shock.http://europepmc.org/articles/PMC3469655?pdf=render |
| spellingShingle | Tammy R Ozment Tuanzhu Ha Kevin F Breuel Tiffany R Ford Donald A Ferguson John Kalbfleisch John B Schweitzer Jim L Kelley Chuanfu Li David L Williams Scavenger receptor class a plays a central role in mediating mortality and the development of the pro-inflammatory phenotype in polymicrobial sepsis. PLoS Pathogens |
| title | Scavenger receptor class a plays a central role in mediating mortality and the development of the pro-inflammatory phenotype in polymicrobial sepsis. |
| title_full | Scavenger receptor class a plays a central role in mediating mortality and the development of the pro-inflammatory phenotype in polymicrobial sepsis. |
| title_fullStr | Scavenger receptor class a plays a central role in mediating mortality and the development of the pro-inflammatory phenotype in polymicrobial sepsis. |
| title_full_unstemmed | Scavenger receptor class a plays a central role in mediating mortality and the development of the pro-inflammatory phenotype in polymicrobial sepsis. |
| title_short | Scavenger receptor class a plays a central role in mediating mortality and the development of the pro-inflammatory phenotype in polymicrobial sepsis. |
| title_sort | scavenger receptor class a plays a central role in mediating mortality and the development of the pro inflammatory phenotype in polymicrobial sepsis |
| url | http://europepmc.org/articles/PMC3469655?pdf=render |
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