Abstract
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.
Highlights
The critically ill patient frequently develops a complex disease spectrum that may include acute respiratory distress syndrome, systemic inflammatory response syndrome, sepsis syndrome and/ or septic shock [1]
In response to cecal ligation and puncture (CLP) sepsis, we found that SRA2/2 mice showed a much longer median survival time (300 hrs vs 43 hrs) than did WT mice
Sepsis induced NF-kB activity is attenuated in the lungs of Scavenger receptor A (SRA) deficient mice To determine if differences in the inflammatory response were responsible for the differences in survival, NFkB activity was measured in WT and SRA2/2 mice in response to CLP by Electrophoretic mobility shift assay (EMSA) (Figure 2)
Summary
The critically ill patient frequently develops a complex disease spectrum that may include acute respiratory distress syndrome, systemic inflammatory response syndrome, sepsis syndrome and/ or septic shock [1]. SRA is primarily expressed by macrophages, though evidence suggests it may be expressed by bone marrow derived and splenic dendritic cells [5]. SRA is a multi-functional receptor which binds endogenous ligands including oxidized LDL and apoptotic cells [5,6,7] and pathogen associated molecular patterns including endotoxin, lipoteichoic acid, and fungal glucans [7,8,9,10,6]. Several reports indicate that SRA interacts with Mer receptor tyrosine kinase [10], Lyn kinase [11] and PTK(Src)/ Rac1/Jnk [12]. It has been reported that SRA induces activation of MyD88 dependent toll like receptor (TLR) 4 signaling and inhibits TLR4 dependent IRF3 activation in response to endotoxin or fucoidan [14]. It has been demonstrated that SRA interacts with TRAF6 upon exposure to Author Summary
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