title: 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.
authors.affiliation: 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.
authors.forename: Sophie
authors.initials: S
authors.lastname: Gilibert
authors.affiliation: 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.
authors.forename: Lauriane
authors.initials: L
authors.lastname: Galle-Treger
authors.affiliation: 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.
authors.forename: Martine
authors.initials: M
authors.lastname: Moreau
authors.affiliation: 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.
authors.forename: Flora
authors.initials: F
authors.lastname: Saint-Charles
authors.affiliation: 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.
authors.forename: Sara
authors.initials: S
authors.lastname: Costa
authors.affiliation: 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.
authors.forename: Raphaëlle
authors.initials: R
authors.lastname: Ballaire
authors.affiliation: 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.
authors.forename: Philippe
authors.initials: P
authors.lastname: Couvert
authors.affiliation: 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.
authors.forename: Alain
authors.initials: A
authors.lastname: Carrié
authors.affiliation: 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.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lesnik
authors.affiliation: 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.
authors.forename: Thierry
authors.initials: T
authors.lastname: Huby
mesh_terms: D000302:Adrenal Cortex / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D008078:Cholesterol, LDL / Q000097:blood / Q000276:immunology / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000097:blood / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology* / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D018482:Muscle, Skeletal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051122:Scavenger Receptors, Class B / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D018805:Sepsis / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D012772:Shock, Septic / Q000276:immunology* / Q000382:microbiology; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016019:Survival Analysis; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000276:immunology / Q000378:metabolism
chemical_list: D008078:Cholesterol, LDL; D015850:Interleukin-6; D008070:Lipopolysaccharides; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10