Adrenocortical Scavenger Receptor Class B Type I Deficiency Exacerbates Endotoxic Shock and Precipitates Sepsis-Induced Mortality in Mice

Abstract

Scavenger receptor class B type I (SR-BI)–deficient mice display reduced survival to endotoxic shock and sepsis. The understanding of the mechanisms underlying SR-BI protection has been hampered by the large spectrum of SR-BI functions and ligands. It notably plays an important role in the liver in high-density lipoprotein metabolism, but it is also thought to participate in innate immunity as a pattern recognition receptor for bacterial endotoxins, such as LPS. In this study, we sought to determine the tissue-specific contribution of SR-BI in the hyperinflammatory response and high mortality rates observed in SR-BI−/− mice in endotoxicosis or sepsis. Restoring plasma levels of high-density lipoprotein, which are critical lipoproteins for LPS neutralization, did not improve acute outcomes of LPS injection in SR-BI−/− mice. Mice deficient for SR-BI in hepatocytes, endothelial cells, or myeloid cells were not more susceptible to LPS-induced death. However, if SR-BI ablation in hepatocytes led to a moderate increase in systemic inflammatory markers, SR-BI deficiency in myeloid cells was associated with an anti-inflammatory effect. Finally, mice deficient for SR-BI in the adrenal cortex, where the receptor provides lipoprotein-derived cholesterol, had impaired secretion of glucocorticoids in response to stress. When exposed to an endotoxin challenge, these mice exhibited an exacerbated systemic and local inflammatory response, reduced activation of atrophy genes in muscle, and high lethality rate. Furthermore, polymicrobial sepsis induced by cecal ligature and puncture resulted in early death of these animals. Our study clearly demonstrates that corticoadrenal SR-BI is a critical element of the hypothalamic-pituitary-adrenal axis to provide effective glucocorticoid-dependent host defense after an endotoxic shock or bacterial infection.

Corticosteroid Therapy Benefits Septic Mice With Adrenal Insufficiency But Harms Septic Mice Without Adrenal Insufficiency*

“…It is worth noting that the SR-BI fl/fl mice display hypomorphism with a 90% decrease in SR-BI expression globally (48), which may contribute to the differential inflammatory response between the hypomSR-BI ∆AC mice and our adrenal-specific SR-BI -/-mice. For example, a decrease in SR-BI expression in the liver impaired LPS clearance, which promotes inflammatory response (29,31). In support of this speculation, an earlier study showed that mice with a dimerization-deficient glucocorticoid receptor (GR dim ) display uncontrolled IL-6 production but has minor effects on TNF-α production in response to LPS (49).…”

“…Thus, the less SR-BI -/-mice death was likely caused by the difference in strain background between the SR-BI -/-(129/B6 mixed background) and wild-type control mice (B6 background) (27). Gilbert et al (31) recently assessed the protective function of adrenal SR-BI using Sf1CreSR-BI fl/fl conditional knockout mice (hypomSR-BI ∆AC ) in B6 background and showed that the hypomSR-BI ∆AC mice lack inducible corticosterone production upon CLP challenge, and the mice are susceptible to CLP-induced animal death. These findings are consistent with our observations.…”

“…Recent studies in our laboratory and others demonstrated that SR-BI is a critical protective factor in sepsis (24)(25)(26)(27)(28)(29)(30)(31). SR-BI is most abundantly expressed in adrenal glands, mediating intracellular cholesterol uptake from HDL for corticosteroid synthesis (22,32).…”

Inflamación y respuesta inmune innata: participación de las lipoproteínas de alta densidad

“…Los niveles plasmáticos de LPS son particularmente importantes en algunas enfermedades como la sepsis, en las cuales se ha observado que el receptor para las HDL, SR-B1, controla la respuesta frente a la endotoxemia, reduciendo la activación de NF-κB (44). De hecho, en ratones con deficiencia en el receptor SR-B1, hay una menor sobrevida cuando se retan con LPS, sugiriendo un papel protector frente a la sepsis (45). Por otra parte, la expresión del TLR4 se ve disminuida en monocitos activados por LPS y tratados con ApoA-I, en los cuales la integridad de las balsas lipídicas se ve afectada por la inducción de flujo de colesterol (46), lo que sugiere que las HDL pueden estar induciendo un cambio funcional en estas células, disminuyendo la respuesta inflamatoria frente al LPS.…”

Role of SR-BI in atherosclerosis, malignancies, and infectious diseases

“…SR-BI knockout mice displayed extreme phenotypes of endotoxic shock and sepsis. Gilibert et al [16] demonstrated that the main role of SR-BI in host defense against endotoxic shock is related to its expression in the adrenal cortex. After endotoxic shock or bacterial infection, adrenal SR-BI, a key component of the hypothalamicpituitary-adrenal axis, effectively provides glucocorticoid-dependent host defense.…”