Ivan Jozic

Stressing the Steroids in Skin: Paradox or Fine-Tuning?

The skin has recently been found to be an extra-adrenal site for glucocorticoid (GC) synthesis that likely acts to modulate local inflammation. Psychological, physiological, and physical stress, both acute and chronic, triggers immune-protective or -damaging responses, including increases in systemic GC levels, which, according to Lin et al. (this issue), may be beneficial in inflammatory skin disease. However, little is known about the interplay between local and systemic production of GCs and the effect of stress (local or systemic) in regulating tissue-specific GC synthesis, its impact on skin homeostasis, and its effect of skin disease.

Skin under the (Spot)-Light: Cross-Talk with the Central Hypothalamic–Pituitary–Adrenal (HPA) Axis

UV radiation is among the most prevalent stressors in humans and diurnal rodents, exerting direct and indirect DNA damage, free-radical production, and interaction with specific chromophores that affects numerous biological processes. In addition to its panoply of effects, UVB (290-320 nm) radiation can specifically affect various local neuroendocrine activities by stimulating the expression of corticotropin-releasing hormone (CRH), urocortin, proopiomelanocortin (POMC), and POMC-derived peptides. Although very little is known about the interplay between the central hypothalamic-pituitary-adrenal (HPA) axis and the skin HPA axis analog, in the current issue Skobowiat and Slominski propose a novel mechanism by which exposure to UVB activates a local HPA axis in skin, which in turn activates the central HPA axis, with the requirement of a functional pituitary gland. This is the first evidence of the local HPA axis in skin contributing to the central neuroendocrine response. This raises intriguing possibilities regarding how local production of cortisol and other HPA axis molecules in skin influence overall systemic levels of cortisol and help regulate local and central HPA axes in the context of homeostasis, skin injury, and inflammatory skin disorders.

Mesenchymal stromal cells prevent bleomycin-induced lung and skin fibrosis in aged mice and restore wound healing

Fibrosis can develop in nearly any tissue leading to a wide range of chronic fibrotic diseases. However, current treatment options are limited. In this study, we utilized an established aged mouse model of bleomycin‐induced lung fibrosis (BLM) to test our hypothesis that fibrosis may develop simultaneously in multiple organs by evaluating skin fibrosis and wound healing. Fibrosis was induced in lung in aged (18–22‐month‐old) C57BL/6 male mice by intratracheal BLM administration. Allogeneic adipose‐derived mesenchymal stromal cells (ASCs) or saline were injected intravenously 24 hr after BLM administration. Full thickness 8‐mm punch wounds were performed 7 days later to study potential systemic anti‐fibrotic and wound healing effects of intravenously delivered ASCs. Mice developed lung and skin fibrosis as well as delayed wound closure. Moreover, we observed similar changes in the expression of known pro‐fibrotic factors in both lung and skin wound tissue, including miR‐199 and protein expression of its corresponding target, caveolin‐1, as well as phosphorylation of protein kinase B. Importantly, ASC‐treated mice exhibited attenuation of BLM‐induced lung and skin fibrosis and accelerated wound healing, suggesting that ASCs may prime injured tissues and prevent end‐organ fibrosis.

Nanoparticles for Fidgety Cell Movement and Enhanced Wound Healing

Complex spatiotemporal interaction of Rho GTPases with microtubules (MTs) and MT-associated proteins drives directed cellular migration. In this issue, Charafeddine et al. describe a role for a novel MT-severing enzyme, fidgetin-like 2 (FL2), in directional migration of keratinocytes and fibroblasts. FL2 normally localizes to the leading edge of the cell cortex where it shears MTs, thus dictating the size and distribution of focal adhesions by regulating cytoskeletal remodeling. Small interfering RNA (siRNA)-directed knockdown of FL2 increases cell migration and focal adhesion area in vitro through possible interaction with Rho GTPases. Efficient FL2 knockdown in murine wounds was achieved using nanoparticles as a siRNA delivery vehicle, and this resulted in enhanced wound closure in vivo. Effective siRNA nanoparticle targeting of MT-severing enzymes offers promise of controlled and targeted delivery that may maximize therapeutic success for patients with burn wounds and chronic wound disorders.