title: 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 high-density lipoprotein 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. Because 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 (hSR-BI) or human SR-BII (hSR-BII). At 6 h after i.p. LPS injection, transgenic hSR-BI and hSR-BII mice demonstrated markedly higher serum levels of proinflammatory cytokines and 2- to 3-fold increased expression levels of inflammatory mediators in the liver and kidney, compared with wild-type (WT) mice. LPS-stimulated inducible NO synthase expression was 3- to 6-fold higher in the liver and kidney of both transgenic strains, although serum NO levels were similar in all mice. Despite the lower high-density lipoprotein 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 MAPK activation in tissues of all mice; however, the strongest response was detected for hepatic extracellular signal-regulated protein kinase 1 and 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 versus 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.
authors.affiliation: Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Irina N
authors.identifier: http://orcid.org/0000-0003-4250-1340
authors.initials: IN
authors.lastname: Baranova
authors.affiliation: Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Ana C P
authors.initials: AC
authors.lastname: Souza
authors.affiliation: Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892; eggermant@niddk.nih.gov abocharov@cc.nih.gov.
authors.forename: Alexander V
authors.identifier: http://orcid.org/0000-0002-3482-2980
authors.initials: AV
authors.lastname: Bocharov
authors.affiliation: Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Tatyana G
authors.initials: TG
authors.lastname: Vishnyakova
authors.affiliation: Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Xuzhen
authors.initials: X
authors.lastname: Hu
authors.affiliation: National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Boris L
authors.identifier: http://orcid.org/0000-0003-0495-2220
authors.initials: BL
authors.lastname: Vaisman
authors.affiliation: National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Marcelo J
authors.identifier: http://orcid.org/0000-0002-9097-2422
authors.initials: MJ
authors.lastname: Amar
authors.affiliation: Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Yana
authors.initials: Y
authors.lastname: Kost
authors.affiliation: National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
authors.affiliation: Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892; National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Amy P
authors.initials: AP
authors.lastname: Patterson
authors.affiliation: Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Peter S T
authors.identifier: http://orcid.org/0000-0001-9557-3909
authors.initials: PS
authors.lastname: Yuen
authors.affiliation: Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Robert A
authors.identifier: http://orcid.org/0000-0003-0940-3079
authors.initials: RA
authors.lastname: Star
authors.affiliation: Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892; Division of Diabetes, Endocrinology, and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Eggerman
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D000818:Animals; D018955:CD36 Antigens / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology*; D008107:Liver Diseases / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D051907:Lysosomal Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051116:Receptors, Scavenger / Q000235:genetics* / Q000378:metabolism
chemical_list: D018955:CD36 Antigens; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D051907:Lysosomal Membrane Proteins; D012333:RNA, Messenger; D051116:Receptors, Scavenger; C074299:SCARB2 protein, human; D019001:Nitric Oxide Synthase; D020928:Mitogen-Activated Protein Kinases