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* Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115;
Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115;
Clinica di Malattie dell’Apparato Respiratorio, Dipartimento Integrato di Oncologia ed Ematologia, Università degli Studi di Modena e Reggio Emilia, Modena, Italy;
Department of Family and Preventive Medicine, University of California San Diego, CA 92101;
¶ Department of Medicine, University of California San Diego, CA 92101;
|| Department of Medical Biochemistry and Molecular Biology, Biocenter Oulu, University of Oulu, Oulu, Finland; and
# Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
The class A scavenger receptors (SR-A) MARCO and SR-AI/II are expressed on lung macrophages (M
s) and dendritic cells (DCs) and function in innate defenses against inhaled pathogens and particles. Increased expression of SR-As in the lungs of mice in an OVA-asthma model suggested an additional role in modulating responses to an inhaled allergen. After OVA sensitization and aerosol challenge, SR-AI/II and MARCO-deficient mice exhibited greater eosinophilic airway inflammation and airway hyperresponsiveness compared with wild-type mice. A role for simple SR-A-mediated Ag clearance ("scavenging") by lung Ms was excluded by the observation of a comparable uptake of fluorescent OVA by wild-type and SR-A-deficient lung Ms and DCs. In contrast, airway instillation of fluorescent Ag revealed a significantly higher traffic of labeled DCs to thoracic lymph nodes in SR-A-deficient mice than in controls. The increased migration of SR-A-deficient DCs was accompanied by the enhanced proliferation in thoracic lymph nodes of adoptively transferred OVA-specific T cells after airway OVA challenge. The data identify a novel role for SR-As expressed on lung DCs in the down-regulation of specific immune responses to aeroallergens by the reduction of DC migration from the site of Ag uptake to the draining lymph nodes.
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1 This work was supported by National Institutes of Health Grants ES0002 and ES11008, and by Department of Defense Grant W81XWH-06-1-0289. M.S.A. is a recipient of the Jere Mead fellowship.
2 Current address: Beth Israel Deaconess Medical Center, Harvard Medical School, 77 Avenue Louis Pasteur, HIM-1039, Boston, MA 02115.
3 M.S.A. and F.F. contributed equally to this work.
4 Address correspondence and reprint requests to Dr. Lester Kobzik, Department of Environmental Health, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115. E-mail address: lkobzik{at}hsph.harvard.edu
5 Abbreviations used in this paper: SR, scavenger receptor; SR-AI/II, SR class A, type I and type II; AHR, airway hyperresponsiveness; AM, alveolar macrophage; BAL, bronchoalveolar lavage; BALF, BAL fluid; Ct, threshold cycle; C3H, C3H/HeJ; DC, dendritic cell; i.t., intratracheal; KO, knockout; LN, lymph node; MARCO, macrophage receptor with collagenous structure; M, macrophage; Penh, enhanced pause; WT, wild type.
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