Tuning Innate Immune Activation by Surface Texturing of Polymer Microparticles: The Role of Shape in Inflammasome Activation

Abstract

Polymeric microparticles have been widely investigated as platforms for delivery of drugs, vaccines, and imaging contrast agents, and are increasingly used in a variety of clinical applications. Microparticles activate the inflammasome complex and induce the processing and secretion of IL-1β, a key innate immune cytokine. Recent work suggests that while receptors are clearly important for particle phagocytosis, other physical characteristics especially shape, play an important role in the way microparticles activate cells. We examined the role of particle surface texturing not only on uptake efficiency but also on the subsequent immune cell activation of the inflammasome. Using a method based on emulsion processing of amphiphilic block copolymers, we prepared microparticles with similar overall sizes and surface chemistries, but having either smooth or highly micro-textured surfaces. In vivo, textured (budding) particles induced more rapid neutrophil recruitment to the injection site. In vitro, budding particles were more readily phagocytosed than smooth particles and induced more lipid raft recruitment to the phagosome. Remarkably, budding particles also induced stronger IL-1β secretion than smooth particles, through activation of the NLRP3 inflammasome. These findings demonstrate a pronounced role of particle surface topography in immune cell activation suggesting that shape is a major determinant of inflammasome activation.

Adenosine monophosphate is elevated in the bronchoalveolar lavage fluid of mice with acute respiratory toxicity induced by nanoparticles with high surface hydrophobicity

“…For example, it has been shown that proteins and opsonins may adsorb more favourably onto a hydrophobic surface, promoting recognition, uptake and inflammatory signaling by phagocytic cells (Ruge et al, 2012;Singh & Lillard, 2009). A pertinent mechanism in this study may be particle aggregation in physiological fluids resulting in irregular surfaces, which have been associated with higher inflammatory potential than comparable smooth-surface particles (Vaine et al, 2013). Only the nanoparticles in the high surface hydrophobicity group (PS50 and PVAc80) aggregated in isotonic buffer at 37 C ( Table 1), suggesting that this may occur to some extent in vivo and contribute to their enhanced toxicity profile.…”

Artefactual Nanoparticle Activation of the Inflammasome Platform: in Vitro Evidence with a Nano-Formed Calcium Phosphate

“…Nanoparticles, whether environmental [6,10], endogenously formed [7,8] or engineered for downstream applications [5,9] have been well studied and clearly linked to inflammasome activation. However, in vitro studies have on occasions been difficult to reconcile with in vivo situations [14,16,40], suggesting that applied in vitro experimental conditions do not always reflect in vivo outcomes.…”

“…In 2006, the late Jurg Tschopp and colleagues reported on the activation of the inflammasome by uric acid and calcium phosphate crystals [4]. Since then, numerous (engineered) nanoparticles have been attributed as inflammasome activators, including silica, titanium dioxide, aluminium hydroxide and calcium phosphates [5][6][7][8][9][10].…”

Biomaterial Strategies for Immunomodulation

“…Studies have shown that elongated particles are trafficked toward the nucleus and are oriented tangentially when compared with spherical particles, which are trafficked quickly and exhibit hexagonal packing in the cell (38, 40). Additionally, budding, or highly textured, microparticles have been shown to activate neutrophils significantly more than smooth particles (41) (Figure 2 a – b ). Further, budding particles were more readily phagocytosed than smooth particles and induced more lipid-raft recruitment to the phagosome.…”