Low-density lipoprotein receptor–related protein 1 attenuates house dust mite–induced eosinophilic airway inflammation by suppressing dendritic cell–mediated adaptive immune responses

• DOI: 10.1016/j.jaci.2017.10.044
• Publication Date: 2017-12-21T03:04:24Z
• Authors: Amarjit Mishra; Xianglan Yao; Ankit Saxena; Elizabeth M. Gordon; Maryann Kaler; Rosemarie A. Cuento; Amisha V. Barochia; Pradeep K. Dagur; J. Philip McCoy; Karen J. Keeran; Kenneth R. Jeffries; Xuan Qu; Zu-Xi Yu; Stewart J. Levine
• Keywords: Adult; Male; 0301 basic medicine; Dermatophagoides pteronyssinus; Mice, Transgenic; Dendritic Cells; Adaptive Immunity; Allergens; Immunoglobulin E; Middle Aged; Asthma; 3. Good health; 03 medical and health sciences; Immunoglobulin G; Eosinophilia; Animals; Humans; Female; Antigens, Dermatophagoides; Bronchoalveolar Lavage Fluid; Low Density Lipoprotein Receptor-Related Protein-1

Low-density lipoprotein receptor-related protein 1 (LRP-1) is a scavenger receptor that regulates adaptive immunity and inflammation. LRP-1 is not known to modulate the pathogenesis of allergic asthma.We sought to assess whether LRP-1 expression by dendritic cells (DCs) modulates adaptive immune responses in patients with house dust mite (HDM)-induced airways disease.LRP-1 expression on peripheral blood DCs was quantified by using flow cytometry. The role of LRP-1 in modulating HDM-induced airways disease was assessed in mice with deletion of LRP-1 in CD11c+ cells (Lrp1fl/fl; CD11c-Cre) and by adoptive transfer of HDM-pulsed CD11b+ DCs from Lrp1fl/fl; CD11c-Cre mice to wild-type (WT) mice.Human peripheral blood myeloid DC subsets from patients with eosinophilic asthma have lower LRP-1 expression than cells from healthy nonasthmatic subjects. Similarly, LRP-1 expression by CD11b+ lung DCs was significantly reduced in HDM-challenged WT mice. HDM-challenged Lrp1fl/fl; CD11c-Cre mice have a phenotype of increased eosinophilic airway inflammation, allergic sensitization, TH2 cytokine production, and mucous cell metaplasia. The adoptive transfer of HDM-pulsed LRP-1-deficient CD11b+ DCs into WT mice generated a similar phenotype of enhanced eosinophilic inflammation and allergic sensitization. Furthermore, CD11b+ DCs in the lungs of Lrp1fl/fl; CD11c-Cre mice have an increased ability to take up HDM antigen, whereas bone marrow-derived DCs display enhanced antigen presentation capabilities.This identifies a novel role for LRP-1 as a negative regulator of DC-mediated adaptive immune responses in the setting of HDM-induced eosinophilic airway inflammation. Furthermore, the reduced LRP-1 expression by circulating myeloid DCs in patients with eosinophilic asthma suggests a possible role for LRP-1 in modulating type 2-high asthma.