Accelerated chemokine receptor 7-mediated dendritic cell migration in Runx3 knockout mice and the spontaneous development of asthma-like disease.
The Runx3 transcription factor is a key regulator of lineage-specific gene expression in several developmental pathways and could also be involved in autoimmunity. We report that, in dendritic cells (DC), Runx3 regulates TGFbeta-mediated transcriptional attenuation of the chemokine receptor CCR7. When Runx3 is lost, i.e., in Runx3 knockout mice, expression of CCR7 is enhanced, resulting in increased migration of alveolar DC to the lung-draining lymph nodes. This increased DC migration and the consequent accumulation of activated DC in draining lymph nodes is associated with the development of asthma-like features, including increased serum IgE, hypersensitivity to inhaled bacterial lipopolysaccharide, and methacholine-induced airway hyperresponsiveness. The enhanced migration of DC in the knockout mice could be blocked in vivo by anti-CCR7 antibodies and by the drug Ciglitazone, known to inhibit CCR7 expression. The data indicate that Runx3 transcriptionally regulates CCR7 and that, when absent, the dysregulated expression of CCR7 in DC plays a role in the etiology of asthmatic conditions that recapitulate clinical symptoms of the human disease. Interestingly, human RUNX3 resides in a region of chromosome 1p36 that contains susceptibility genes for asthma and hypersensitivity against environmental antigens. Thus, mutations in RUNX3 may be associated with increased sensitivity to asthma development.
Fainaru
Ofer
O
Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel.
Shseyov
David
D
Hantisteanu
Shay
S
Groner
Yoram
Y
D000818:Animals; D001249:Asthma / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers; D003713:Dendritic Cells / Q000378:metabolism*; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D008198:Lymph Nodes / Q000473:pathology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045162:Thiazolidinediones / Q000494:pharmacology
C515370:CCR7 protein, human; C515371:Ccr7 protein, mouse; D050677:Core Binding Factor Alpha 3 Subunit; D017931:DNA Primers; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; C493730:Runx3 protein, mouse; D045162:Thiazolidinediones; C039671:ciglitazone