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.

Propionibacterium acnes is a critical component in the pathogenesis of acne vulgaris, stimulating the production of various inflammatory mediators, such as cytokines and chemokines, important in the local inflammatory response found in acne. This study explored the role of P. acnes and its ability to induce matrix metalloproteinases (MMPs) in primary human monocytes and how this induction is regulated by retinoids. MMP-1- and MMP-9-expressing cells were present in perifollicular and dermal inflammatory infiltrates within acne lesions, suggesting their role in acne pathogenesis. In vitro, we found that P. acnes induced MMP-9 and MMP-1 mRNA, and the expression of MMP-9, but not of MMP-1, was found to be Toll-like receptor 2-dependent. P. acnes induced the mRNA expression of tissue inhibitors of metalloproteinase (TIMP)-1, the main regulator of MMP-9 and MMP-1. Treatment of monocytes with all-trans retinoic acid (ATRA) significantly decreased baseline MMP-9 expression. Furthermore, co-treatment of monocytes with ATRA and P. acnes inhibited MMP-9 and MMP-1 induction, while augmenting TIMP-1 expression. These data indicate that P. acnes-induced MMPs and TIMPs may be involved in acne pathogenesis and that retinoic acid modulates MMP and TIMP expression, shifting from a matrix-degradative phenotype to a matrix-preserving phenotype.

Propionibacterium acnes is a major etiological factor of acne, triggering an inflammatory response in part through the activation of TLR2. In this study, we demonstrate that activation of peripheral blood monocytes with P. acnes in vitro induced their differentiation into two distinct innate immune cell subsets, CD209+ macrophages and CD1b+ dendritic cells. Furthermore, P. acnes induced expression of mRNA for the cytokines IL-15 and GM-CSF, which differentiate CD209+ and CD1b+ cells, respectively. The CD209+ cells were more effective in uptake of P. acnes, compared with the CD1b+ cells, and demonstrated a 2-fold greater antimicrobial activity against the phagocytosed bacteria. Although CD1b+ cells secreted inflammatory cytokines in response to both P. acnes and a TLR2 ligand control, the CD209+ cells responded only to P. acnes. The addition of all-trans retinoic acid, a commonly used agent for the treatment of acne, directly induced differentiation of monocytes into CD209+ macrophages and enhanced the P. acnes-mediated differentiation of the CD209+ subset. Therefore, the differentiation of monocytes into CD209+ macrophages and CD1b+ dendritic cells distinctly mediate the innate immune response to P. acnes.

Skeletal muscle morphogenesis depends upon interactions between developing muscle fibers and the extracellular matrix (ECM) that anchors fibers to the myotendinous junction (MTJ). The pathways that organize the ECM and regulate its engagement by cell-matrix adhesion complexes (CMACs) are therefore essential for muscle integrity. Here, we demonstrate the impact of transmembrane protein 2 (tmem2) on cell-matrix interactions during muscle morphogenesis in zebrafish. Maternal-zygotic tmem2 mutants (MZtmem2) exhibit muscle fiber detachment, in association with impaired laminin organization and ineffective fibronectin degradation at the MTJ. Similarly, disorganized laminin and fibronectin surround MZtmem2 cardiomyocytes, which could account for their hindered movement during cardiac morphogenesis. In addition to ECM defects, MZtmem2 mutants display hypoglycosylation of α-dystroglycan within the CMAC, which could contribute to the observed fiber detachment. Expression of the Tmem2 ectodomain can rescue aspects of the MZtmem2 phenotype, consistent with a possible extracellular function of Tmem2. Together, our results suggest that Tmem2 regulates cell-matrix interactions by affecting both ECM organization and CMAC activity. These findings evoke possible connections between the functions of Tmem2 and the etiologies of congenital muscular dystrophies, particularly dystroglycanopathies.