Human SR-BI and SR-BII Potentiate Lipopolysaccharide-Induced Inflammation and Acute Liver and Kidney Injury in Mice

Abstract

The class B scavenger receptors BI (SR-BI) and BII (SR-BII) are HDL receptors that recognize various pathogens, including bacteria and their products. It has been reported that SR-BI/II-null mice are more sensitive than normal mice to endotoxin-induced inflammation and sepsis. Since the SR-BI/II-knockout model demonstrates multiple immune and metabolic disorders we investigated the role of each receptor in the LPS-induced inflammatory response and tissue damage using transgenic mice with pLiv-11-directed expression of human SR-BI or SR-BII. Six hours after intraperitoneal LPS injection, transgenic hSR-BI and hSR-BII mice demonstrated markedly higher serum levels of pro-inflammatory cytokines and 2-3-fold increased expression levels of inflammatory mediators in the liver and kidney, compared to wild type (WT) mice. LPS-stimulated iNOS expression was 3-6-fold higher in the liver and kidney of both transgenic strains, although serum NO levels were similar in all mice. Despite the lower HDL plasma levels, both transgenic strains responded to LPS by a 5-fold increase of plasma corticosterone levels which were only moderately lower than in WT animals. LPS treatment resulted in MAPKs activation in tissues of all mice; however, the strongest response was detected for hepatic ERK1/2 and kidney JNK of both transgenic mice. Histological examination of hepatic and renal tissue from LPS-challenged mice revealed more injury in hSR-BII but not hSR-BI transgenic mice vs WT controls. Our findings demonstrate that hSR-BII, and to a lesser extent hSR-BI, significantly increase LPS-induced inflammation and contribute to LPS-induced tissue injury in the liver and kidney, two major organs susceptible to LPS toxicity.

Exploiting scavenger receptors in cancer immunotherapy: Lessons from CD5 and SR‐B1

“…This system abrogates the expression of the IFN-α when the anti-tumor immune response is achieved, eliminating the transgenic viruses that express the IFN-α and the SR-B1 ligand. A third case of the cooperation between SR-B1 and TLR has been reported in which SR-B1 and its splicing variant has been implicated in acute kidney injury mediated by LPS [84]. In that report, transgenic mice overexpressing these molecules and treated with LPS have higher serum levels of pro-inflammatory cytokines.…”

“…The second mechanism is based on the capacity of SR-B1 to trigger an intracellular signaling cascade that leads to increased tumor cell proliferation. In this regard, activation of the PI3K/AKT pathway by SR-B1 ligands provides an essential survival signal for tumor cells [84,85]. A third mechanism of SR-B1 to promote tumor growth is by the inhibition of acute inflammation [73,74].…”

“…SR-B1 can promote tumor progression through three different mechanisms. The first mechanism is based on the direct role of SR-B1 as a lipid transporter, increasing tumor cholesterol and lipid content, thereby contributing to tumor nutrition and growth [83,84]. The second mechanism is based on the capacity of SR-B1 to trigger an intracellular signaling cascade that leads to increased tumor cell proliferation.…”

Synthetic Amphipathic Helical Peptides Targeting CD36 Attenuate Lipopolysaccharide-Induced Inflammation and Acute Lung Injury

“…It is established that the TLR system makes the major contribution to inflammatory responses in many of these cases (24), including ALI (25). However, recent data demonstrate that SR-Bs, especially CD36, may significantly facilitate inflammatory responses during endotoxemia (26,27) and sepsis (28). We propose that these two receptor systems act in a complementary manner in the pulmonary response to pathogen associated molecular patterns.…”

Geno Protective and Anti-Apoptotic Effect of Green Tea Against Perinatal Lipopolysaccharide-Exposure Induced Liver Toxicity in Rat Newborns

“…Whereas, injury, damage, and sepsis of various organs, such as liver was attributed to the endotoxicity of lipopolysaccharide (LPS) that is present as a major glycolipid component of the outer cell wall of gram-negative bacteria (Baranova et al, 2016). It has been reported previously that, LPS-induced injury in the liver and systemic circulation was linked to the release of toxic mediators such as cytokines, interleukins, as well as increases in oxidative stress parameters as superoxide radicals and nitric oxide (NO) (Ojiako et al, 2015).…”