AUTHOR=Hildebrand Dagmar , Metz-Zumaran Camila , Jaschkowitz Greta , Heeg Klaus TITLE=Silencing SOCS1 via Liposome-Packed siRNA Sustains TLR4-Ligand Adjuvant JOURNAL=Frontiers in Immunology VOLUME=10 YEAR=2019 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.01279 DOI=10.3389/fimmu.2019.01279 ISSN=1664-3224 ABSTRACT=

Infectious diseases remain one of the leading causes of death worldwide. Vaccination is a powerful instrument to avert a variety of those by inducing a pathogen-specific immune response and ensure a long-lasting protection against the respective infection. Nevertheless, due to increasing numbers of immunocompromised patients and emergence of more aggressive pathogens existing vaccination techniques are limited. In our study we investigated a new strategy to strengthen vaccine adjuvant in order to increase immunity against infectious diseases. The strategy is based on an amplification of Toll-like receptor 4 (TLR4) -induced activation of antigen-presenting cells (APCs) by turning off a powerful endogenous inhibitor of APC-activation. TLR4 signaling induces the release of cytokines that bind autocrine and paracrine to receptors, activating the Janus kinase (JAK) 2/signal transducers and activators of transcription (STAT) 3 cascade. Subsequently, STAT3 induces expression of suppressor of cytokine signaling (SOCS) 1 that terminates the inflammatory response. In the approach, TLR4-adjuvant monophosphoryl lipid A (MPLA)-stimulated monocyte-activation is reinforced and sustained by silencing SOCS1 via lipid nanoparticle-enclosed siRNA (L-siRNA). L-siRNA is transported into primary cells without any toxic side effects and protected from early degradation. Through lipid core-embedded functional groups the lipid particle escapes from endosomes and releases the siRNA when translocated into the cytoplasm. SOCS1 is potently silenced, and SOCS1-mediated termination of NFκB signaling is abrogated. Consequently, the MPLA-stimulated activation of APCs, monitored by release of pro-inflammatory cytokines such as IL-6, TNFα, and IL-1β, upregulation of MHC class II molecules and costimulatory CD80/CD86 is strongly enhanced and prolonged. SOCS1-silenced APCs, pulsed with liposomal tetanus light chain toxin (TeTxLC) antigen, activate autologous T cells much more intensively than SOCS1-expressing cells. Importantly, expansion of cocultured CD4+ as well as CD8+ T cells is remarkably enhanced. Furthermore, our results point toward a broad T helper cell response as TH1 typical as well as TH2 characteristic cytokines are elevated. Taken together, this study in the human system comprises a translational potential to develop more effective vaccines against infectious diseases by inhibition of the endogenous negative-feedback loop in APCs.