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. Here, 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 homologue 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 (WT) 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 to the adoptive transfer of HDM-pulsed, CD11c+ BMDCs from WT 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.

Secretoglobin Superfamily Protein SCGB3A2 Alleviates House Dust Mite-Induced Allergic Airway Inflammation in Mice

“…Single cell suspensions of mediastinal lymph nodes (MLNs) from either saline- or HDM-challenged mice were prepared by filtering through a 100 μm-cell strainer, as previously described [22]. After red blood cells were lysed with Red Blood Cell Lysing Buffer (Sigma-Aldrich), MLN cells were re-suspended in RPMI-1640 medium supplemented with 10% fetal bovine serum, 2 mM L-glutamine, 100 IU/mL penicillin, 100 μg/mL streptomycin, 250 ng/mL amphotericin B and 3.5 μL/L 2-mercaptoethanol.…”

Network study of nasal transcriptome profiles reveals master regulator genes of asthma

“…This is a schematic of molecular interactions between the master regulators of the cilium assembly module. Functional activity and relationships based on prior literature (solid arrows) [45][46][47][48][49][55][56][57][58][59] and novel interactions identified by this study's probabilistic causal gene network (dashed arrows) are shown. FOXJ1 (shown in red) was a master regulator gene in the ARIA-1 cohort of children with severe persistent asthma and the ATOM cohort of adults with mild/moderate asthma.…”

Very low-density lipoprotein receptor increases in a liver-specific manner due to protein deficiency but does not affect fatty liver in mice

“…However, it could not be concluded that increased VLDLR in protein deficiency affected inflammation because plasma ALT concentration or expression of inflammatory marker genes in the liver was not affected by Vldlr deficiency. In addition, many studies have reported that VLDLR promotes inflammation, and few suppress it 36 . Further studies are required to clarify the role of VLDLR in the liver under protein-restriction.…”