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

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.

Effects of Lipoxin A4 on antimicrobial actions of neutrophils in sepsis

“…In addition, we performed gram stains on the blood bacteria grown on tryptic soy agar. The predominant bacteria present were Lactobacilli and Escherichia coli (Supplemental data) which was completely consistent with published work by other investigators [38].…”

CXCL1 Contributes to Host Defense in Polymicrobial Sepsis via Modulating T Cell and Neutrophil Functions

“…We found reduced activity of NF-κB in the organs from cxcl1 −/− mice post-CLP. Although NF-κB activity is important for survival after PMS (4, 30), it is questionable whether this phenomenon contributes to efficient neutrophil recruitment and bacterial clearance. NF-κB activation has been demonstrated to be essential for neutrophil recruitment due to its contribution to the expression of adhesion molecules, such as ICAM-1 (31).…”

“…However, the molecular and cellular mechanisms that regulate immune responses to polymicrobial sepsis are not completely understood. Prior studies have shown that deletion of nucleotide-binding oligomerization domain-2 (NOD2) receptors or the scavenger receptor class A leads to host protection (3, 4). In contrast, reduced survival and diminished production of cytokines and chemokineswas observed in Stat-2 −/− mice during lipopolysaccharide (LPS)-mediated endotoxic shock, indicating a crucial role for STAT-2 in host defense (5).…”

Scavenger receptor SRA attenuates microglia activation and protects neuroinflammatory injury in intracerebral hemorrhage

“…Scavenger receptor SRA is expressed primarily on myeloid cells, including DCs, and functions as an innate pattern recognition receptor (Ozment et al, 2012;Yu et al, 2011;Seimon et al, 2006). In addition to the established roles that SRA plays in lipid metabolism, atherosclerosis and pathogen recognition, the evidence also demonstrates that SRA serves as a suppressor of vaccine-induced antitumor immunity Qian et al, 2011;Guo et al, 2012).…”