Absence of Smad3 Induces Neutrophil Migration after Cutaneous Irradiation

Abstract

Our previous work showed that 6 weeks after cutaneous irradiation, mice null (knockout, KO) for Smad3, a cytoplasmic downstream mediator of transforming growth factor-beta, demonstrate less epidermal acanthosis and dermal inflammation than wild-type (WT) Smad3 mice. Analysis of the kinetics of inflammation showed that 6 to 8 hours after skin irradiation, there was a transient sevenfold increase in neutrophil influx in Smad3 KO mice compared with WT. Herein we describe bone marrow transplantation and skin grafting between WT and KO mice to assess the contribution of the neutrophil genotype compared with that of irradiated skin to the induction of neutrophil migration after irradiation. Results from bone marrow transplantation showed that WT marrow transplanted into KO mice enhanced neutrophil migration 6 to 8 hours after irradiation by 3.2-fold compared with KO marrow in WT mice. KO skin grafted onto either WT or KO animals showed a sixfold elevation of neutrophils after irradiation compared with grafted WT skin. These results suggest that the genotype of the irradiated skin, rather than the inflammatory cell, controls neutrophil influx. Circulating neutrophils, increased in WT mice after injection of granulocyte colony-stimulating factor, resulted in increased neutrophil migration to the skin 6 to 8 hours after irradiation and less skin damage 6 weeks after irradiation compared with untreated WT mice. Thus, early responses, including enhanced neutrophil influx, appear to contribute to subsequent cutaneous radioprotection.

Cigarette smoke exposure aggravates air space enlargement and alveolar cell apoptosis inSmad3knockout mice

“…Interestingly, cell counts decreased after 8 wk CS in Smad3 Ϫ/Ϫ mice, while they at the same time significantly increased in CS-exposed Smad3 ϩ/ϩ . This observation points perhaps toward a dysregulated immune response following continuous CS challenge, which is in line with previous studies showing that TGF-␤ signaling via Smad3 is required for an appropriate regulation of the immune response, in particular for normal T-lymphocyte and neutrophil activity (13,28,55). It is also plausible that release of elastolytic enzymes from neutrophils contribute to the progression of emphysema and perpetuate inflammatory cell recruitment to the lung.…”

The Impact of the Myeloid Response to Radiation Therapy

“…Interestingly, exogenous administration of either GM-CSF or G-CSF to animals can provide some protection against lethal radiation doses [127–129] and has been delivered to patients following radiation accidents [130]. In addition to hematopoietic recovery, the effect of these growth factors may relate to neutrophil migration to irradiated sites and subsequently improved repair of radiation damage [131]. These data fit with the repair role of myeloid cells in the tumor discussed earlier, and in this context of cancer-driven myeloid expansion, GM-CSF and G-CSF may improve recovery of the tumor from radiation damage, permitting outgrowth of residual cancer cells.…”

The TG-interacting Factor TGIF1 Regulates Stress-induced Proinflammatory Phenotype of Endothelial Cells

“…Transgenic mouse models with reduced proinflammatory radiation response are not necessarily associated with tissue radioprotection. For example, SMAD3 Ϫ/Ϫ mice are protected against radiation-induced skin injury despite a transient strong increase in neutrophil influx (24,25). In the same way, we recently showed that radiation proctitis is attenuated in mast cell-deficient mice compared with WT mice and that it is associated with increased tissue neutrophil influx and expression of several inflammatory mediators immediately after radiation exposure (26).…”