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J Immunol. 2014 Jul 15;193(2):817-26. doi: 10.4049/jimmunol.1303164. Epub 2014 Jun 16.

Adrenocortical scavenger receptor class B type I deficiency exacerbates endotoxic shock and precipitates sepsis-induced mortality in mice.

Author information

1
INSERM Unité Mixte de Recherche_S 1166, Hôpital de la Pitié-Salpêtrière, F-75013, Paris, France; Université Pierre et Marie Curie 06, Unité Mixte de Recherche_S 1166, F-75013, Paris, France; Institute of Cardiometabolism and Nutrition, F-75013, Paris, France; and.
2
INSERM Unité Mixte de Recherche_S 1166, Hôpital de la Pitié-Salpêtrière, F-75013, Paris, France; Université Pierre et Marie Curie 06, Unité Mixte de Recherche_S 1166, F-75013, Paris, France; Institute of Cardiometabolism and Nutrition, F-75013, Paris, France; and Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Service d'Endocrinologie-Métabolisme, F-75013 Paris, France.
3
INSERM Unité Mixte de Recherche_S 1166, Hôpital de la Pitié-Salpêtrière, F-75013, Paris, France; Université Pierre et Marie Curie 06, Unité Mixte de Recherche_S 1166, F-75013, Paris, France; Institute of Cardiometabolism and Nutrition, F-75013, Paris, France; and Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Service d'Endocrinologie-Métabolisme, F-75013 Paris, France thierry.huby@upmc.fr.

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.

PMID:
24935924
DOI:
10.4049/jimmunol.1303164
[Indexed for MEDLINE]
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