Runx3 regulates mouse TGF-beta-mediated dendritic cell function and its absence results in airway inflammation.
Runx3 transcription factor regulates cell lineage decisions in thymopoiesis and neurogenesis. Here we report that Runx3 knockout (KO) mice develop spontaneous eosinophilic lung inflammation associated with airway remodeling and mucus hypersecretion. Runx3 is specifically expressed in mature dendritic cells (DC) and mediates their response to TGF-beta. In the absence of Runx3, DC become insensitive to TGF-beta-induced maturation inhibition, and TGF-beta-dependent Langerhans cell development is impaired. Maturation of Runx3 KO DC is accelerated and accompanied by increased efficacy to stimulate T cells and aberrant expression of beta2-integrins. Lung alveoli of Runx3 KO mice accumulate DC characteristic of allergic airway inflammation. Taken together, abnormalities in DC function and subset distribution may constitute the primary immune system defect, which leads to the eosinophilic lung inflammation in Runx3 KO mice. These data may help elucidate the molecular mechanisms underlying the pathogenesis of allergic airway inflammation in humans.
Fainaru
Ofer
O
Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel.
Woolf
Eilon
E
Lotem
Joseph
J
Yarmus
Merav
M
Brenner
Ori
O
Goldenberg
Dalia
D
Negreanu
Varda
V
Bernstein
Yael
Y
Levanon
Ditsa
D
Jung
Steffen
S
Groner
Yoram
Y
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D018821:CD18 Antigens / Q000096:biosynthesis; D002478:Cells, Cultured; D050677:Core Binding Factor Alpha 3 Subunit; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D003713:Dendritic Cells / Q000378:metabolism* / Q000473:pathology; D004804:Eosinophils / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009093:Mucus / Q000378:metabolism; D011014:Pneumonia / Q000276:immunology* / Q000473:pathology; D011650:Pulmonary Alveoli / Q000473:pathology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*
D018821:CD18 Antigens; D050677:Core Binding Factor Alpha 3 Subunit; D004268:DNA-Binding Proteins; C493730:Runx3 protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta