title: The very low density lipoprotein receptor attenuates house dust mite-induced airway inflammation by suppressing dendritic cell-mediated adaptive immune responses.
abstract: The very low density lipoprotein receptor (VLDLR) is a member of the low-density lipoprotein receptor family that binds multiple ligands and plays a key role in brain development. Although the VLDLR mediates pleiotropic biological processes, only a limited amount of information is available regarding its role in adaptive immunity. In this study, we identify an important role for the VLDLR in attenuating house dust mite (HDM)-induced airway inflammation in experimental murine asthma. We show that HDM-challenged Vldlr(-/-) mice have augmented eosinophilic and lymphocytic airway inflammation with increases in Th2 cytokines, C-C chemokines, IgE production, and mucous cell metaplasia. A genome-wide analysis of the lung transcriptome identified that mRNA levels of CD209e (DC-SIGNR4), a murine homolog of DC-SIGN, were increased in the lungs of HDM-challenged Vldlr(-/-) mice, which suggested that the VLDLR might modify dendritic cell (DC) function. Consistent with this, VLDLR expression by human monocyte-derived DCs was increased by HDM stimulation. In addition, 55% of peripheral blood CD11c(+) DCs from individuals with allergy expressed VLDLR under basal conditions. Lastly, the adoptive transfer of HDM-pulsed, CD11c(+) bone marrow-derived DCs (BMDCs) from Vldlr(-/-) mice to the airways of wild type recipient mice induced augmented eosinophilic and lymphocytic airway inflammation upon HDM challenge with increases in Th2 cytokines, C-C chemokines, IgE production, and mucous cell metaplasia, as compared with the adoptive transfer of HDM-pulsed, CD11c(+) BMDCs from wild type mice. Collectively, these results identify a novel role for the VLDLR as a negative regulator of DC-mediated adaptive immune responses in HDM-induced allergic airway inflammation.
authors.affiliation: Laboratory of Asthma and Lung Inflammation, Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Karin
authors.initials: K
authors.lastname: Fredriksson
authors.forename: Amarjit
authors.initials: A
authors.lastname: Mishra
authors.forename: Jonathan K
authors.initials: JK
authors.lastname: Lam
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Mushaben
authors.forename: Rosemarie A
authors.initials: RA
authors.lastname: Cuento
authors.forename: Katharine S
authors.initials: KS
authors.lastname: Meyer
authors.forename: Xianglan
authors.initials: X
authors.lastname: Yao
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Keeran
authors.forename: Gayle Z
authors.initials: GZ
authors.lastname: Nugent
authors.forename: Xuan
authors.initials: X
authors.lastname: Qu
authors.forename: Zu-Xi
authors.initials: ZX
authors.lastname: Yu
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Yang
authors.forename: Nalini
authors.initials: N
authors.lastname: Raghavachari
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Dagur
authors.forename: J Philip
authors.initials: JP
authors.lastname: McCoy
authors.forename: Stewart J
authors.initials: SJ
authors.lastname: Levine
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D039521:CD11c Antigen / Q000235:genetics / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D004804:Eosinophils / Q000276:immunology / Q000473:pathology; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007073:Immunoglobulin E / Q000235:genetics / Q000276:immunology; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D039981:Pyroglyphidae; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology; D011973:Receptors, LDL / Q000235:genetics / Q000276:immunology*; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D039521:CD11c Antigen; D015815:Cell Adhesion Molecules; D016207:Cytokines; D007073:Immunoglobulin E; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D011973:Receptors, LDL; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C036053:VLDL receptor
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