Nitric oxide (NO) is a short-lived, diatomic, lipophilic gas that plays an integral role in defending against pathogens. Among its many functions are involvement in immune cell signaling and in the biochemical reactions by which immune cells defend against bacteria, fungi, viruses and parasites. NO signaling directs a broad spectrum of processes, including the differentiation, proliferation, and apoptosis of immune cells. When secreted by activated immune cells, NO diffuses across cellular membranes and exacts nitrosative and oxidative damage on invading pathogens. These observations led to the development of NO delivery systems that can harness the antimicrobial properties of this evanescent gas. The innate microbicidal properties of NO, as well as the antimicrobial activity of the various NO delivery systems, are reviewed.

Advances in nanotechnology have demonstrated potential application of nanoparticles for effective and targeted drug delivery. Here, we investigated the antimicrobial and immunological properties and the feasibility of using nanoparticles to deliver antimicrobial agents to treat a cutaneous pathogen. Nanoparticles synthesized with chitosan and alginate demonstrated a direct antimicrobial activity in vitro against Propionibacterium acnes, the bacterium linked to the pathogenesis of acne. By electron microscopy imaging, chitosan-alginate nanoparticles were found to induce disruption of the P. acnes cell membrane, providing a mechanism for the bactericidal effect. The chitosan-alginate nanoparticles also exhibited anti-inflammatory properties as they inhibited P. acnes induced inflammatory cytokine production in human monocytes and keratinocytes. Furthermore, benzoyl peroxide, a commonly used anti-acne drug, was effectively encapsulated in the chitosan-alginate nanoparticles and demonstrated superior antimicrobial activity against P. acnes compared to benzoyl peroxide alone while demonstrating less toxicity to eukaryotic cells. Together, these data suggest the potential utility of topical delivery of chitosan-alginate nanoparticle encapsulated drug therapy for the treatment of dermatologic conditions with infectious and inflammatory components.

Wound healing is a complex process driven largely by the migration of a variety of distinct cell types from the wound margin into the wound zone. In this study, we identify the previously uncharacterized microtubule-severing enzyme, Fidgetin-like 2 (FL2), as a fundamental regulator of cell migration that can be targeted in vivo using nanoparticle-encapsulated siRNA to promote wound closure and regeneration. In vitro, depletion of FL2 from mammalian tissue culture cells results in a more than two-fold increase in the rate of cell movement, due in part to a significant increase in directional motility. Immunofluorescence analyses indicate that FL2 normally localizes to the cell edge, importantly to the leading edge of polarized cells, where it regulates the organization and dynamics of the microtubule cytoskeleton. To clinically translate these findings, we utilized a nanoparticle-based siRNA delivery platform to locally deplete FL2 in both murine full-thickness excisional and burn wounds. Topical application of FL2 siRNA nanoparticles to either wound type results in a significant enhancement in the rate and quality of wound closure both clinically and histologically relative to controls. Taken together, these results identify FL2 as a promising therapeutic target to promote the regeneration and repair of cutaneous wounds.

TNF-like weak inducer of apoptosis (TWEAK, TNFSF12) and its sole receptor Fn14, belonging to the TNF ligand and receptor superfamilies respectively, are involved in cell survival and cytokine production. The role of TWEAK/Fn14 interactions in the pathogenesis of cutaneous lupus has not been explored. TWEAK treatment of murine PAM212 keratinocytes stimulated the secretion of RANTES via Fn14, and promoted apoptosis. Parthenolide, but not wortmanin or the MAPK inhibitor PD98059, significantly decreased production of RANTES, indicating that this effect of TWEAK is mediated via NF-κB signaling. Ultraviolet-B irradiation significantly upregulated the expression of Fn14 on keratinocytes in vitro and in vivo, and increased RANTES production. MRL/lpr Fn14 knockout lupus mice were compared with MRL/lpr Fn14 wild-type mice to evaluate for any possible differences in the severity of cutaneous lesions and the presence of infiltrating immune cells. MRL/lpr Fn14 knockout mice had markedly attenuated cutaneous disease as compared to their Fn14 wild-type littermates, as evidenced by the well maintained architecture of the skin and significantly decreased skin infiltration of T cells and macrophages. Our data strongly implicate TWEAK/Fn14 signaling in the pathogenesis of the cutaneous manifestations in the MRL/lpr model of spontaneous lupus, and suggest a possible target for therapeutic intervention.

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In patients with MS, sexual dysfunction has a much larger detrimental impact on the mental health aspects of HrQoL than severity of physical disability.

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