Aminated nanomicelles as a designer vaccine adjuvant to trigger inflammasomes and multiple arms of the innate immune response in lymph nodes

Abstract

In this study, we suggest a designer vaccine adjuvant that can mimic the drainage of pathogens into lymph nodes and activate innate immune response in lymph nodes. By the amination of multivalent carboxyl groups in poly-(γ-glutamic acid) (γ-PGA) nanomicelles, the size was reduced for rapid entry into lymphatic vessels, and the immunologically inert nanomicelles were turned into potential activators of inflammasomes. Aminated γ-PGA nanomicelles (aPNMs) induced NLRP3 inflammasome activation and the subsequent release of proinflammatory IL-1β. The NLRP3-dependent inflammasome induction mechanism was confirmed through enzyme (cathepsin B and caspase-1) inhibitors and NLRP3 knockout mice model. After the aPNMs were combined with a clinically evaluated TLR3 agonist, polyinosinic–polycytidylic acid sodium salt (aPNM-IC), they triggered multiple arms of the innate immune response, including the secretion of pro-inflammatory cytokines by both inflammasomes and an inflammasome-independent pathway and the included type I interferons.

RNA-Seq Analysis of Spinal Cord Tissues from hPFN1G118V Transgenic Mouse Model of ALS at Pre-symptomatic and End-Stages of Disease

“…Previous transcriptomic studies of murine models and of post-mortem human ALS tissues also identified upregulation of inflammatory processes 9 , 10 , 13 , 26 , 27 . Inflammasomes are multiprotein complexes that are activated by a variety of factors and induce activation of caspase-1, which mediates production of pro-inflammatory cytokines interleukin-1B and interleukin-18, inducers of pyropoptosis, a highly inflammatory form of programmed cell death 28 . Genes encoding caspase-1 and apoptosis-associated speck-like protein containing a CARD (ASC, also known as PYCARD), which are components of all types of inflammasome complexes, were significantly up-regulated in end-stage PFN1 G118V spinal cords 29 .…”

“…AIM2 and NAIP2 transcripts, which are present in AIM2 inflammasomes and NLRC4 inflammasomes, respectively, also were up-regulated in tissues of PFN1 G118V mice at end-stage 29 . The NLRP3 inflammasome complex has been characterized most extensively and implicated in ALS and other neurodegenerative diseases that include Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, and Huntington’s disease 28 , 30 – 32 . Investigations of human ALS tissue samples and SOD1 mouse models have shown up-regulation of NLRP3 inflammasome activity 31 , 32 .…”

Nanoparticle Platforms for Antigen-Specific Immune Tolerance

“…Many studies of using this type of nanoparticles for antigen presentation have focused on targeting lymph nodes, based on the rationale that a high density of antigen present cells is present at this location. Smaller nanoparticles (<30 nm) are capable of draining in lymphatic capillaries in a size-dependent fashion (96). In one study, 25 and 100 nm nanoparticles were tested, with a much higher accumulation in dendritic cells seen with the smaller 25 nm particles (97).…”

The sixth revolution in pediatric vaccinology: immunoengineering and delivery systems

“… 23 – 25 Activation of the inflammasome through cytosolic NOD-like receptors (NLRs) can lead to a self-adjuvant effect by the nanoparticle vehicle itself that promotes adaptive immunity. 26 – 28 Lastly, nanoparticles containing vaccines can be used to control the duration of delivery through synchronous and sustained release of antigens and adjuvants. 29 , 30 Delivery kinetics can be further modified using strategies such as incorporating nanoparticles into hydrogels or intradermal microneedle delivery systems.…”

“…Furthermore, the targeting of nanoparticles carrying TLR agonists to endosomes leads to activation of endosomal TLRs, promoting strong Th1-type responses (24)(25)(26). Activation of the inflammasome through cytosolic NOD-like receptors can lead to a self-adjuvant effect by the nanoparticle vehicle itself that promotes adaptive immunity (27)(28)(29). Lastly, nanoparticles containing vaccines can be used to control the duration of delivery through synchronous and sustained release of antigens and adjuvants (30,31).…”