Selective control of SIRP-alpha-positive airway dendritic cell trafficking through CD47 is critical for the development of T(H)2-mediated allergic inflammation.
BACKGROUND
Dendritic cells (DCs) are essential for the initiation and maintenance of T(H)2 responses to inhaled antigen that lead to the establishment of allergic diseases. Two subpopulations of nonplasmacytoid DCs (ie, CD11b(low)CD103+ and CD11b(high)CD103(-)) are found in lung/airway tissues. Yet the identification and migratory properties of the DC subset that contributes to T(H)2-mediated responses remain to be clarified. CD47, a signal regulatory protein (SIRP)-alpha partner, reportedly governed skin DC migration.


OBJECTIVE
We here thought to investigate the role of CD47/SIRP-alpha interactions in airway DC trafficking and the development of allergic airway inflammation.


METHODS
We characterized the DC influx into lungs and mediastinal lymph nodes in CD47(-/-) and CD47(+/+) BALB/c mice by using experimental models of allergic asthma. Mice were systemically (intraperitoneal ovalbumin/alum) or locally (intratracheal ovalbumin-loaded bone marrow-derived DCs) immunized and challenged by ovalbumin aerosol. We also evaluated the consequences of SIRP-alpha-Fc fusion molecule administration on the induction of airway disease in BALB/c mice.


RESULTS
SIRP-alpha selectively identified the CD11b(high)CD103(-) DC subset that predominantly accumulated in mediastinal lymph nodes during airway inflammation. However, CD103(-)SIRP-alpha+ DC trafficking, T(H)2 responses, and airway disease were impaired in CD47(-/-) mice. Importantly, the adoptive transfer of CD103(-) SIRP-alpha+CD47(+/+) but not CD47(-/-) DCs elicited a strong T(H)2 response in CD47(-/-) mice. Finally, the administration of SIRP-alpha-Fc molecule protected BALB/c mice from allergic airway inflammation.


CONCLUSIONS
Lung CD11b(high)CD103(-)SIRP-alpha+ DC migration is governed by self-CD47 expression, and manipulation of the CD47/SIRP-alpha pathway suppresses CD103(-)SIRP-alpha(+) DC-driven pathogenic T(H)2 responses and airway inflammation.
Raymond
Marianne
M
Immunoregulation Laboratory, Centre Hospitalier de l'Université de Montréal Research Center, Hôpital Notre-Dame, Montreal, Quebec, Canada.
Rubio
Manuel
M
Fortin
Geneviève
G
Shalaby
Karim Hamdy
KH
Hammad
Hamida
H
Lambrecht
Bart N
BN
Sarfati
Marika
M
D019264:Adoptive Transfer; D000818:Animals; D051928:CD47 Antigen / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006967:Hypersensitivity / Q000276:immunology* / Q000378:metabolism; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D011971:Receptors, Immunologic / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
D051928:CD47 Antigen; C497895:Cd47 protein, mouse; D016207:Cytokines; C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; D010047:Ovalbumin