Transcription factor T-bet regulates skin sclerosis through its function in innate immunity and via IL-13.
Tissue remodeling with fibrosis is a predominant pathophysiological mechanism of many human diseases. Systemic sclerosis is a rare, often lethal, disorder of unknown etiology manifested by dermal fibrosis (scleroderma) and excessive connective tissue deposition in internal organs. Currently, there are no available antifibrotic therapeutics, a reflection of our lack of understanding of this process. Animal models of scleroderma are useful tools to dissect the transcription factors and cytokines that govern fibrosis. A disproportionate increase of type 2 cytokines, like TGF-beta and IL-4, more than type 1 cytokines, like IFN-gamma, is thought to underlie the pathogenesis of scleroderma. In this study, we show that mice deficient in the transcription factor T-box expressed in T cells (T-bet), a master regulator of type 1 immunity, display increased sensitivity to bleomycin-induced dermal sclerosis. Despite the well-established role of T-bet in adaptive immunity, we also show that RAG2(-/-) mice, which lack T and B cells, are vulnerable to bleomycin-induced scleroderma and that RAG2/T-bet double-deficient mice maintain the increased sensitivity to bleomycin observed in T-bet(-/-) mice. Furthermore, overexpression of T-bet in T cells does not affect the induction of skin sclerosis in this model. Lastly, we show that IL-13 is the profibrotic cytokine regulated by T-bet in this model. Together, we conclude that T-bet serves as a repressor of dermal sclerosis through an IL-13-dependent pathway in innate immune cells. T-bet, and its transcriptional network, represent an attractive target for the treatment of systemic sclerosis and other fibrosing disorders.
Aliprantis
Antonios O
AO
Department of Infectious Diseases and Immunology, Harvard School of Public Health, 651 Huntington Avenue, Boston, MA 02115, USA.
Wang
Jingsong
J
Fathman
John W
JW
Lemaire
Raphael
R
Dorfman
David M
DM
Lafyatis
Robert
R
Glimcher
Laurie H
LH
D000818:Animals; D001761:Bleomycin; D016207:Cytokines / Q000378:metabolism; D005355:Fibrosis; D007107:Immune System; D007113:Immunity, Innate / Q000276:immunology*; D018793:Interleukin-13 / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000473:pathology; D012598:Sclerosis; D012867:Skin / Q000473:pathology*; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000378:metabolism*; D000098815:T-bet Transcription Factor
D016207:Cytokines; D018793:Interleukin-13; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D001761:Bleomycin