LRP-1 Attenuates House Dust Mite-induced Eosinophilic Airway Inflammation by Suppressing Dendritic Cell-mediated Adaptive Immune Responses

Publication date: Available online 21 December 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): 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
BackgroundThe LDL-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.ObjectiveTo assess whether LRP-1 expression by dendritic cells (DCs) modulates adaptive immune responses in house dust mite (HDM)-induced airways disease.MethodsLRP-1 expression on peripheral blood DCs was quantified by flow cytometry. The role of LRP-1 in modulating HDM-induced airways disease was assessed in mice with a deletion of LRP-1 in CD11c⁺ cells (Lrp1^fl/fl; CD11c-Cre) and by the adoptive transfer of HDM-pulsed CD11b⁺ DCs from Lrp1^fl/fl; CD11c-Cre mice to wild-type mice.ResultsHuman peripheral blood myeloid DC subsets from eosinophilic asthmatics have lower LRP-1 expression than cells from healthy, non-asthmatic subjects. Similarly, LRP-1 expression by CD11b⁺ lung DCs was significantly reduced in HDM-challenged wild-type mice. HDM-challenged LRP-1^fl/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 wild-type mice generated a similar phenotype of enhanced eosinophilic inflammation and allergic sensitization. Furthermore, CD11b⁺ DCs in the lungs of Lrp1^fl/fl; CD11c-Cre mice have an increased ability to take up HDM antigen, whereas bone marrow-derived DCs display enhanced antigen presentation capabilities.ConclusionThis identifies a novel role for LRP-1 as a negative regulator of DC-mediated adaptive immune responses in HDM-induced eosinophilic airway inflammation. Furthermore, the reduced LRP-1 expression by circulating myeloid DCs from eosinophilic asthmatics suggests a possible role for LRP-1 in modulating type 2-high asthma.

Graphical abstract

http://ift.tt/2CUbHjG