Scavenger Receptor Class A Plays a Central Role in Mediating Mortality and the Development of the Pro-Inflammatory Phenotype in Polymicrobial Sepsis

PLoS Pathogens

Donald A. Ferguson¹  Jim L. Kelley²  John Kalbfleisch³  Kevin F. Breuel⁴  Tiffany R. Ford⁴  John B. Schweitzer⁵  Chuanfu Li⁶  Tammy R. Ozment⁶  David L. Williams⁶  Tuanzhu Ha⁶ 

[1] Department of Biomedical Sciences, East Tennessee State University, Quillen College of Medicine, Johnson City, Tennessee, United States of America;Department of Internal Medicine, East Tennessee State University, Quillen College of Medicine, Johnson City, Tennessee, United States of America;Department of Medical Education, East Tennessee State University, Quillen College of Medicine, Johnson City, Tennessee, United States of America;Department of Obstetrics and Gynecology, East Tennessee State University, Quillen College of Medicine, Johnson City, Tennessee, United States of America;Department of Pathology, East Tennessee State University, Quillen College of Medicine, Johnson City, Tennessee, United States of America;Department of Surgery, East Tennessee State University, Quillen College of Medicine, Johnson City, Tennessee, United States of America

关键词: Sepsis;    Mouse models;    Inflammation;    Lactobacillus;    Cytokines;    Apoptosis;    Blood;    Neutrophils;   

DOI  :  10.1371/journal.ppat.1002967

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY