Amarjit Mishra1, Xianglan Yao1, Ankit Saxena2, Elizabeth M Gordon1, Maryann Kaler1, Rosemarie A Cuento1, Amisha V Barochia1, Pradeep K Dagur2, J Philip McCoy2, Karen J Keeran3, Kenneth R Jeffries3, Xuan Qu4, Zu-Xi Yu4, Stewart J Levine5. 1. Laboratory of Asthma and Lung Inflammation, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. 2. Flow Cytometry Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. 3. Animal Surgery and Resources Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. 4. Pathology Core Facility, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. 5. Laboratory of Asthma and Lung Inflammation, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. Electronic address: levines@nhlbi.nih.gov.
Abstract
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. Published by Elsevier Inc.
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-Cremice 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-Cremice 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-Cremice 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. Published by Elsevier Inc.
Entities:
Keywords:
Low-density lipoprotein receptor–related protein 1; dendritic cells; eosinophilic airway inflammation; house dust mite; type 2–high asthma
Authors: Shyra J Gardai; Yi-Qun Xiao; Matthew Dickinson; Jerry A Nick; Dennis R Voelker; Kelly E Greene; Peter M Henson Journal: Cell Date: 2003-10-03 Impact factor: 41.582
Authors: Ludwig T Weckbach; Anita Gola; Michael Winkelmann; Sascha M Jakob; Leopold Groesser; Julia Borgolte; Frank Pogoda; Robert Pick; Monika Pruenster; Josef Müller-Höcker; Elisabeth Deindl; Markus Sperandio; Barbara Walzog Journal: Blood Date: 2014-01-23 Impact factor: 22.113
Authors: Manikandan Subramanian; Crystal D Hayes; Joseph J Thome; Edward Thorp; Glenn K Matsushima; Joachim Herz; Donna L Farber; Kang Liu; Madepalli Lakshmana; Ira Tabas Journal: J Clin Invest Date: 2014-02-10 Impact factor: 14.808
Authors: Julian Casciano; Jerry A Krishnan; Mary Buatti Small; Philip O Buck; Gokul Gopalan; Chenghui Li; Robert Kemp; Zenobia Dotiwala Journal: BMC Pulm Med Date: 2016-07-13 Impact factor: 3.317
Authors: Cody E Nichols; John S House; Huiling Li; James M Ward; Annah Wyss; Jason G Williams; Leesa J Deterding; Jennifer A Bradbury; Laura Miller; Darryl C Zeldin; Stephanie J London Journal: Am J Respir Cell Mol Biol Date: 2021-03 Impact factor: 6.914