We have identified that apolipoprotein E serves as an endogenous negative regulator of airway hyperreactivity and goblet cell hyperplasia in asthma by a low density lipoprotein receptor(LDLR)-dependent mechanism (Apolipoprotein E Negatively Regulates House Dust Mite-induced Asthma via a LDL Receptor-mediated Pathway. Yao X, Fredriksson K, Yu ZX, Xu X, Raghavachari N, Keeran KJ, Zywicke GJ, Kwak M, Amar MJ, Remaley AT, Levine SJ. Am J Respir Crit Care Med. 2010 Jul 9. Epub ahead of print). The effects of apoE, which is synthesized by macrophages in the lung, are mediated via binding to LDLRs that are expressed on ciliated airway epithelial cells. This project will utilize apolipoprotein receptor knock-out mice to define the role of other apolipoprotein receptors in modulating the pathogenesis of asthma. Furthermore, the mechanisms by which asthma pathogenesis is modulated by lung apolipoprotein receptors will be characterized. This research has identified (1) a novel role for the very low density lipoprotein receptor in allergic asthma by regulating dendritic cell function. In particular, we have shown that the very low density lipoprotein receptor is expressed by circulating human dendritic cells (DC) and attenuates DC-mediated adaptive immune responses in HDM-induced airway inflammation (Journal of Immunology 2014; 192: 4497) and (2) the interaction between apolipoprotein A-I and its receptor, the ABCA1 transporter, attenuates ovalbumin-induced neutrophilic airway inflammation by suppressing granulocyte colony-stimulating factor production by pulmonary vascular endothelial cells and alveolar macrophages (Am J Respir Cell Mol Biol, 2014, 51:626-36). LRP-1 is a scavenger-type endocytic receptor that binds multiple ligands. We have shown that LRP-1 plays an important role in modulating dendritic cell (DC) function during house dust mite (HDM)-induced allergic airway inflammation with the following findings: (i.) Myeloid dendritic cells from the blood of eosinophil-high asthmatics, as well as CD11b+ DCs from the lungs of HDM-challenged mice, have reduced LRP-1 expression, (ii.) the adoptive transfer of HDM-pulsed LRP-1-deficient CD11b+ DCs to nave wild-type mice increases eosinophilic airway inflammation following HDM challenges, (iii.) HDM-challenged mice with a specific deletion of LRP-1 in CD11c+ cells, which include DCs and alveolar macrophages, have increased eosinophilic airway inflammation, allergic sensitization, TH2 cytokine production, and mucous metaplasia, and (iv.) LRP-1-deficient DCs show increased uptake and presentation of HDM antigen. Thus, these findings identify LRP-1 as a novel negative regulator of DC-mediated adaptive immunity in HDM-induced eosinophilic airway inflammation and suggest that LRP-1 might modulate the type 2-high asthma endotype in humans. This project has been epublished ahead of print in the Journal of Allergy and Clinical Immunology (Dec 21,2017).
