Abstract
Lysine (K) type cationic lipid with a propyl spacer and ditetradecyl hydrophobic moieties composing liposomes, K3C14, previously studied for gene delivery, were reported to activate the NLRP3 inflammasomes in human macrophages via the conventional phagolysosomal pathway. In this study, K3C16, a propyl spacer bearing lysine type lipids with dihexadecyl moieties (an extension of two hydrocarbon tail length) were compared with K3C14 as liposomes. Such a small change in tail length did not alter the physical properties such as size distribution, zeta potential and polydispersity index (PDI). The NLRP3 activation potency of K3C16 was shown to be 1.5-fold higher. Yet, the toxicity was minimal, whereas K3C14 has shown to cause significant cell death after 24 h incubation. Even in the presence of endocytosis inhibitors, cytochalasin D or dynasore, K3C16 continued to activate the NLRP3 inflammasomes and to induce IL-1β release. To our surprise, K3C16 liposomes were confirmed to fuse with the plasma membrane of human macrophages and CHO-K1 cells. It is demonstrated that the change in hydrophobic tail length by two hydrocarbons drastically changed a cellular entry route and potency in activating the NLRP3 inflammasomes.
Highlights
With the growing demand of harnessing human body’s natural defense systems to treat various diseases, nanoparticles such as silica dioxide, titanium dioxide [1] and engineered nanomaterials (ENMs) [2] were investigated in their abilities to activate inflammasomes
K3C16 was barely toxic to cells, which was indicated with a % cytotoxicity below the natural cause of cell death after 24 h incubation; on the other hand, K3C14 caused nearly 80% cell death (Fig. 1b)
With the presence of NLRP3 inhibitor or Caspase-1 inhibitor, CRID3 or VX765, respectively, we demonstrated that both K3C14 and K3C16 triggered IL-1β release was primarily NLPR3 and Caspase-1 dependent (Fig. 1c and d)
Summary
With the growing demand of harnessing human body’s natural defense systems to treat various diseases, nanoparticles such as silica dioxide, titanium dioxide [1] and engineered nanomaterials (ENMs) [2] were investigated in their abilities to activate inflammasomes. Activation of the NLRP3 inflammasomes followed by secretion of IL-1β links the innate immunity to the adaptive immunity via the recruitment of both leukocytes and lymphocytes [9]. It is an attractive target for immunotherapy. The lead assembly, K3C14, bearing lipids with a propyl spacer and ditetradecyl hydrophobic moiety displayed the highest degree of NLRP3 inflammasome activation among the investigated subjects. Lysine type cationic lipids with ditetradecyl or dihexadecyl hydrophobic moiety were reported showing improved transfection efficiency with lower toxicity as lipoplexes [14]. It is to our interest to explore its structural effect and mechanism in activating the NLRP3 inflammasomes alongside with K3C14
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