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

• Published in: Journal of allergy and clinical immunology Vol. 142; no. 4; pp. 1066 - 1079.e6
• Main Authors: Mishra, Amarjit, Yao, Xianglan, Saxena, Ankit, Gordon, Elizabeth M., Kaler, Maryann, Cuento, Rosemarie A., Barochia, Amisha V., Dagur, Pradeep K., McCoy, J. Philip, Keeran, Karen J., Jeffries, Kenneth R., Qu, Xuan, Yu, Zu-Xi, Levine, Stewart J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2018; Elsevier Limited
• Subjects: Adaptive Immunity; Adoptive transfer; Adult; Allergens - immunology; Allergies; Animals; Antigen presentation; Antigens, Dermatophagoides - immunology; Apolipoproteins; Asthma; Asthma - blood; Asthma - immunology; Asthma - physiopathology; Bone marrow; Bronchoalveolar Lavage Fluid - cytology; CD11b antigen; CD11c antigen; Clonal deletion; Cloning; Dendritic cells; Dendritic Cells - immunology; Dermatophagoides pteronyssinus - immunology; Dust; Eosinophilia - blood; Eosinophilia - immunology; Eosinophilia - physiopathology; eosinophilic airway inflammation; Female; Flow cytometry; Genotype & phenotype; Growth factors; house dust mite; Human subjects; Humans; Immune response; Immunoglobulin E - blood; Immunoglobulin G - blood; Inflammation; Leukocytes (eosinophilic); Lipoproteins; Low Density Lipoprotein Receptor-Related Protein-1 - immunology; Low-density lipoprotein receptor–related protein 1; Lymphocytes; Lymphocytes T; Male; Metaplasia; Mice, Transgenic; Middle Aged; Pathogenesis; Peripheral blood; Phenotypes; Proteins; Receptor density; Respiratory tract; Respiratory tract diseases; Rodents; Scavenger receptors; type 2–high asthma; TCR; PAS; type 2–high asthma; CLR; AHR; MDC; MLN; HDM; NF-κB; moDC; dendritic cells; BMDC; LDL; DC-SIGN; VLDL; TLR; WT; SSC; house dust mite; HSP; AF; BALF; Treg; CFSE; BAL; eosinophilic airway inflammation; pDC; APC; NHLBI; Low-density lipoprotein receptor–related protein 1; PE; MHCII; LRP-1; OVA; Foxp3; PerCP; cDCs; DC
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2017.10.044

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. [Display omitted]