Contribution of Particle-Induced Lysosomal Membrane Hyperpolarization to Lysosomal Membrane Permeabilization

Abstract

Lysosomal membrane permeabilization (LMP) has been proposed to precede nanoparticle-induced macrophage injury and NLRP3 inflammasome activation; however, the underlying mechanism(s) of LMP is unknown. We propose that nanoparticle-induced lysosomal hyperpolarization triggers LMP. In this study, a rapid non-invasive method was used to measure changes in lysosomal membrane potential of murine alveolar macrophages (AM) in response to a series of nanoparticles (ZnO, TiO2, and CeO2). Crystalline SiO2 (micron-sized) was used as a positive control. Changes in cytosolic potassium were measured using Asante potassium green 2. The results demonstrated that ZnO or SiO2 hyperpolarized the lysosomal membrane and decreased cytosolic potassium, suggesting increased lysosome permeability to potassium. Time-course experiments revealed that lysosomal hyperpolarization was an early event leading to LMP, NLRP3 activation, and cell death. In contrast, TiO2- or valinomycin-treated AM did not cause LMP unless high doses led to lysosomal hyperpolarization. Neither lysosomal hyperpolarization nor LMP was observed in CeO2-treated AM. These results suggested that a threshold of lysosomal membrane potential must be exceeded to cause LMP. Furthermore, inhibition of lysosomal hyperpolarization with Bafilomycin A1 blocked LMP and NLRP3 activation, suggesting a causal relation between lysosomal hyperpolarization and LMP.

Surface-Functionalized Polystyrene Nanoparticles Alter the Transmembrane Potential via Ion-Selective Pores Maintaining Global Bilayer Integrity

“… 23 , 112 Precedent toxicological studies have demonstrated that NPs could break the cell cycle by inducing not only the most common membrane depolarization 23 , 113 but also hyperpolarization. 114 , 115 The fact that cationic NPs are usually more toxic to cells than anionic ones 1 , 15 , 116 , 117 could be tentatively explained in terms of our findings. We have shown that PS-NH 2 has the most potent capacity of membrane disruption, pointing all our findings to membrane depolarization by different mechanisms.…”

“…As regard to NP-induced toxicity, the selective hydrophilic pores created by PS NPs point to a more complex modulation of transmembrane electric potential as summarized in the cartoon of Figure . Cell membranes are characterized by a net negative charge on the cytosolic side of the membrane (usually −40 to −70 mV) that changes during cell proliferation and differentiation. , Precedent toxicological studies have demonstrated that NPs could break the cell cycle by inducing not only the most common membrane depolarization , but also hyperpolarization. , The fact that cationic NPs are usually more toxic to cells than anionic ones ,,, could be tentatively explained in terms of our findings. We have shown that PS-NH 2 has the most potent capacity of membrane disruption, pointing all our findings to membrane depolarization by different mechanisms.…”

The Effects of Curcumin on Inflammasome: Latest Update

“…IL-1β levels were reduced in bronchoalveolar lavage (BAL) fluids from animals previously treated with nanoparticles and treated in vitro with C. phaeocaulis . C. phaeocaulis has an anti-inflammatory effect against lung disease associated with excessive activation of the NLRP3 inflammasome/inflammation [ 61 , 62 ].…”

Association between Microorganisms and Microplastics: How Does It Change the Host–Pathogen Interaction and Subsequent Immune Response?

“…If the process described above occurs in antigen-presenting cells (macrophages or dendritic cells), microorganisms can be processed within the vesicles and generate peptides to be presented in the class II context, thereby initiating a strong antibody response. Then, upon vesicle rupture, microorganism components can be released into the cytoplasm, favoring their presentation in the context of class I molecules and generating cytotoxic T cell responses [ 114 , 115 ]. Thus, the presence of MPs may actually broaden the breadth of specific adaptive immunity against microorganisms by promoting both class II- and class I-dependent specific immunity.…”