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The intestinal microvasculature (iMV) plays multiple pathogenic roles during chronic inflammatory bowel disease (IBD). The iMV acts as a second line of defense and is, among other factors, crucial for the innate immunity in the gut. It is also the therapeutic location in IBD targeting aggravated leukocyte adhesion processes involving ICAM-1 and E-selectin. Specific targeting is stressed via nanoparticulate drug vehicles. Evaluating the iMV in enterocyte barrier models in vitro could shed light on inflammation and barrier-integrity processes during IBD. Therefore, we generated a barrier model by combining the enterocyte cell line Caco-2 with the microvascular endothelial cell line ISO-HAS-1 on opposite sides of a transwell filter-membrane under culture conditions which mimicked the physiological and inflamed conditions of IBD. The IBD model achieved a significant barrier-disruption, demonstrated via transepithelial-electrical resistance (TER), permeability-coefficient (Papp) and increase of sICAM sE-selectin and IL-8. In addition, the impact of a prospective model drug-vehicle (silica nanoparticles, aSNP) on ongoing inflammation was examined. A decrease of sICAM/sE-selectin was observed after aSNP-exposure to the inflamed endothelium. These findings correlated with a decreased secretion of ICAM/E-selectin bearing exosomes/microvesicles, as evaluated via ELISA. Our findings indicate that aSNP treatment of the inflamed endothelium during IBD may hamper exosomal/microvesicular systemic communication.
Nature achieves diverse biological functions through structure formation. Inspired by the controlled formation of polypeptide nanostructures in cells, synthetic methods have been developed to assemble artificial nanostructures and organelle-like compartments within living cells. While these synthetic intracellular assemblies have mostly been used to disrupt cellular processes, their potential to induce a gain of function within cells remains unexplored. Here, we introduce redox-sensitive isopeptides that transform into self-assembling linear peptides inside human cytotoxic T cells in response to intracellular levels of glutathione. The in situ formation of synthetic peptide nanostructures in cytotoxic T cells leads to cellular stiffening, establishing a direct interface between biochemically driven peptide assembly and mechanobiological effects. This change in biophysical properties, along with increased phosphorylation of signaling proteins associated with T cell activation, correlates with a significant enhancement in the efficacy of cytotoxic T cells to eliminate cancer cells. Our findings elucidate the cellular impact of synthetic peptide nanostructures assembled within living cytotoxic T cells and demonstrate their ability to modulate and enhance effector immune cell responses.
