Matrix-Bound Nanovesicles Promote Prohealing Immunomodulation Without Immunosuppression

Abstract

Bioscaffolds composed of extracellular matrix (ECM) have been shown to promote a profound transition in macrophages and T-cells from a proinflammatory to a prohealing phenotype with associated site-appropriate and constructive tissue remodeling rather than scar tissue formation. Matrix-bound nanovesicles (MBV) are a distinct class of extracellular vesicles that can be isolated from the ECM and can recapitulate these immunomodulatory effects on myeloid cells in vitro and in vivo, as shown in multiple preclinical models of inflammatory-driven diseases. However, the effect of this MBV-mediated immunomodulation upon the ability to mount an adaptive immune response following pathogenic challenge is unknown. The present study assessed the humoral immune response with and without repeated MBV administration in a mouse model of Streptococcus pneumoniae vaccination and infection. Mice were immunized on day 0, followed by an intraperitoneal MBV or methotrexate (MTRX) injection the next day and weekly thereafter for 5 weeks. Antipneumococcal polysaccharide immuglobulin G and immuglobulin M titers were no different between the vaccine + MBV and the vaccine-only groups, in contrast to the decreased titers in the MTRX-treatment group. Fifty percent of animals treated with MBV were protected from lethal septic infection with S. pneumoniae, and MBV treatment altered the population of immune cells within the lung following sublethal intranasal infection. Macrophages derived from bone marrow mononuclear cells harvested from MBV-treated mice showed persistent immunomodulatory effects following ex vivo challenge with bacterial antigens. The results of this study show that MBV treatment does not compromise the ability to mount an adaptive immune response and suggest that MBV induce sustained immunomodulation in cells of the myeloid lineage. Impact Statement The current study shows the immunomodulatory effect of matrix-bound nanovesicles (MBV) on vaccinated mice, while demonstrating their compatibility with the adaptative immune system. Furthermore, results of this study suggest a sustained MBV-mediated immunomodulation on myeloid lineages, which could be used in the development of future vaccines and immunomodulatory therapies.

Keywords: adaptive immunity; bacterial infection; extracellular matrix; extracellular vesicle; immunomodulation; innate immunity; matrix-bound nanovesicles.