Smad7 Ameliorates TGFβ-mediated Skin Inflammation And Associated Wound Healing Defects
Li BIAN, Fulun Li, Shunsuke Iriyama, Zhe Jian, Bin Fan, Jing Jing Luo, Dongyan D Wang, Christian D. Young, Gangwen Han, Xiao-Jing Wang.
UNIVERSITY OF COLORADO ANSCHUTZ MEDICAL CAMPUS, AURORA, CO, USA.
We assessed roles of Smad7 in skin inflammation and wound healing using genetic and pharmacological approaches. In K5.TGFβ1/K5.Smad7 bigenic (double transgenic) mice, Smad7 transgene expression reversed TGFβ1 transgene-induced inflammation, fibrosis and subsequent epidermal hyperplasia, and molecularly abolished TGFβ and NF-κB activation. Next, we produced recombinant human Smad7 protein with a Tat-tag (Tat-Smad7) that rapidly permeates cells. Tat-Smad7 subcutaneous injection attenuated infiltrated F4/80+ and CD11b+ leukocytes and αSMA+ fibroblasts prior to attenuating epidermal hyperplasia in K5.TGFβ1 skin. Further, topically applied Tat-Smad7 on wounds of K5.TGFβ1 skin accelerated wound closure with improved re-epithelialization and reductions in inflammation and fibrotic response. A short treatment with Tat-Smad7 was also sufficient to reduce TGFβ and NF-κB signaling in K5.TGFβ1 skin and wounds. Relevant to clinic, we found that human diabetic wounds had elevated TGFβ and NF-κB signaling compared to normal skin. To assess the oncogenic risk of a potential Smad7-based therapy, we exposed K5.Smad7 skin to chemical carcinogenesis and found reductions in myeloid leukocyte infiltration in tumors but not accelerated carcinogenesis compared to wildtype littermates. Our study suggests the feasibility of using exogenous Smad7 below an oncogenic level to alleviate skin inflammation and wound healing defects associated with excessive activation of TGFβ and NF-κB.
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