Inflammasome-activating nanoparticles as modular systems for optimizing vaccine efficacy

Abstract

Innate immune system activation is a critical step in the initiation of an effective adaptive immune response; therefore, activation of a class of innate pathogen receptors called pattern recognition receptors (PRR) is a central feature of many adjuvant systems. It has recently been shown that one member of an intracellular PRR, the NLRP3 inflammasome, is activated by a number of classical adjuvants including aluminum hydroxide and saponins [1,2]. Inflammasome activation in vitro requires signaling of both the Toll-like receptor (TLR) and NLRP3 in antigen-presenting cells. Here we present a class of nanomaterials endowed with these two signals for rapid optimization of vaccine design. We constructed this system using a simple approach that incorporates lipopolysaccharides (LPS) onto the surface of nanoparticles constructed from a biocompatible polyester, poly (lactic-coglycolic acid) (PLGA), loaded with antigen. We demonstrate that LPS-modified particles are preferentially internalized by dendritic cells compared to uncoated nanoparticles and the system, when administered to mice, elicits potent humoral and cellular immunity against a model antigen, ovalbumin. Wild type macrophages pulsed with LPS-modified nanoparticles resulted in production of the proinflammatory cytokine IL-1β consistent with inflammasome activation. In comparison, NLRP3-deficient and caspase-1-deficient macrophages showed negligible production of IL-1β. Furthermore, when endocytosis and lysosomal destabilization were inhibited, inflammasome activity was diminished, supporting the notion that nanoparticles rupture lysosomal compartments and behave as 'danger signals' [3]. The generality of this vaccination approach is tested by encapsulation of a recombinant West Nile envelope protein and demonstrated by protection against a murine model of West Nile encephalitis. The design of such an antigen delivery mechanism with the ability to

Photosensitizer and Light Pave the Way for Cytosolic Targeting and Generation of Cytosolic CD8 T Cells Using PLGA Vaccine Particles

“…The polymer type, the surface decoration of the particles, as well as further excipients and adjuvants all represent factors that enable the modulation of the immunological properties of a particle-based Ag delivery system (35,(46)(47)(48)(49)(50)(51)(52). In studies in which PLGA microparticles were shown to stimulate APCs associated with the release of Ags into the cytosol as consequence of destabilization of the endosomal membrane (53)(54)(55).…”

Inflammasome components Asc and caspase-1 mediate biomaterial-induced inflammation and foreign body response

“…In addition to these biologically formed materials, other small particulates such as alum, silica, asbestos, and nanoparticles have been shown to result in inflammasome activation (13)(14)(15). These materials have very different physical characteristics but are small enough to be phagocytosed, and subsequent phagosome rupture has been shown to result in inflammasome activation and production of IL-1β and IL-18 (16).…”

Caspase-1 Activity in Microglia Stimulated by Pro-Inflammagen Nanocrystals

“…This state of "frustrated phagocytosis" leads to the disruption of lysosomes and subsequently initiates the activation of NLRP-3 receptors to form inflammasomes. 2 The delayed but robust increase in caspase-1 activity by LPSÀQDs is thus likely due to the activation of inflammasome resulting from the frustrated phagocytosis.…”

“…1 Inflammation can be induced by numerous exogenous agents, including airborne particles, biological aggregates, nanocrystals (quantum dots (QDs)) and lipopolysaccharides (LPS). 2 These inflammagens are recognized by macrophages and microglia and some of them bind to cell surface receptors such as Toll-like receptors (TLR). In particular, endotoxins, including LPS, bind TLR-4 and trigger receptor dimerization at the plasma membrane, which, in turn, activate signal transduction cascades to induce inflammation.…”