title: Key role for scavenger receptor B-I in the integrative physiology of host defense during bacterial pneumonia.
abstract: Scavenger receptor B-I (SR-BI) is a multirecognition receptor that regulates cholesterol trafficking and cardiovascular inflammation. Although it is expressed by neutrophils (PMNs) and lung-resident cells, no role for SR-BI has been defined in pulmonary immunity. Herein, we report that, compared with SR-BI(+/+) counterparts, SR-BI(-/-) mice suffer markedly increased mortality during bacterial pneumonia associated with higher bacterial burden in the lung and blood, deficient induction of the stress glucocorticoid corticosterone, higher serum cytokines, and increased organ injury. SR-BI(-/-) mice had significantly increased PMN recruitment and cytokine production in the infected airspace. This was associated with defective hematopoietic cell-dependent clearance of lipopolysaccharide from the airspace and increased cytokine production by SR-BI(-/-) macrophages. Corticosterone replacement normalized alveolar neutrophilia but not alveolar cytokines, bacterial burden, or mortality, suggesting that adrenal insufficiency derepresses PMN trafficking to the SR-BI(-/-) airway in a cytokine-independent manner. Despite enhanced alveolar neutrophilia, SR-BI(-/-) mice displayed impaired phagocytic killing. Bone marrow chimeras revealed this defect to be independent of the dyslipidemia and adrenal insufficiency of SR-BI(-/-) mice. During infection, SR-BI(-/-) PMNs displayed deficient oxidant production and CD11b externalization, and increased surface L-selectin, suggesting defective activation. Taken together, SR-BI coordinates several steps in the integrated neutrophilic host defense response to pneumonia.
authors.affiliation: Division of Intramural Research, Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Gowdy
authors.affiliation: Division of Intramural Research, Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Madenspacher
authors.affiliation: Division of Intramural Research, Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Azzam
authors.affiliation: Division of Intramural Research, Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Gabor
authors.affiliation: 1] Cellular and Molecular Pathology Branch, National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA [2] Integrated Laboratory Systems, Inc., National Institutes of Health, Research Triangle Park, North Carolina, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Janardhan
authors.affiliation: Division of Intramural Research, Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Aloor
authors.affiliation: Division of Intramural Research, Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: Fessler
mesh_terms: D000311:Adrenal Glands / Q000276:immunology / Q000473:pathology; D000818:Animals; D058491:Bacterial Load; D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology; D039481:CD11b Antigen / Q000235:genetics / Q000276:immunology; D003345:Corticosterone / Q000096:biosynthesis / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D005786:Gene Expression Regulation; D007710:Klebsiella Infections / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D007711:Klebsiella pneumoniae / Q000276:immunology; D019041:L-Selectin / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D018410:Pneumonia, Bacterial / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D051122:Scavenger Receptors, Class B / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D016019:Survival Analysis
chemical_list: D039481:CD11b Antigen; D016207:Cytokines; D008070:Lipopolysaccharides; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D019041:L-Selectin; D003345:Corticosterone