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


OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSION
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.
['Mishra|Amarjit|A|', 'Yao|Xianglan|X|', 'Saxena|Ankit|A|', 'Gordon|Elizabeth M|EM|', 'Kaler|Maryann|M|', 'Cuento|Rosemarie A|RA|', 'Barochia|Amisha V|AV|', 'Dagur|Pradeep K|PK|', 'McCoy|J Philip|JP|', 'Keeran|Karen J|KJ|', 'Jeffries|Kenneth R|KR|', 'Qu|Xuan|X|', 'Yu|Zu-Xi|ZX|', 'Levine|Stewart J|SJ|']
D056704:Adaptive Immunity D000328:Adult D000485:Allergens D000818:Animals D039741:Antigens, Dermatophagoides D001249:Asthma D001992:Bronchoalveolar Lavage Fluid D003713:Dendritic Cells D040002:Dermatophagoides pteronyssinus D004802:Eosinophilia D005260:Female D006801:Humans D007073:Immunoglobulin E D007074:Immunoglobulin G D026503:Low Density Lipoprotein Receptor-Related Protein-1 D008297:Male D008822:Mice, Transgenic D008875:Middle Aged
eosinophilic airway inflammation dendritic cells house dust mite Low-density lipoprotein receptor–related protein 1 type 2–high asthma