Triclosan disrupts immune cell function by depressing Ca 2+ influx following acidification of the cytoplasm

• Published in: Toxicology and applied pharmacology Vol. 405; p. 115205
• Main Authors: Sangroula, Suraj, Baez Vasquez, Alan Y, Raut, Prakash, Obeng, Bright, Shim, Juyoung K, Bagley, Grace D, West, Bailey E, Burnell, John E, Kinney, Marissa S, Potts, Christian M, Weller, Sasha R, Kelley, Joshua B, Hess, Samuel T, Gosse, Julie A
• Format: Journal Article
• Language: English
• Published: United States 15.10.2020
• Subjects: Anti-Infective Agents - toxicity; Calcium - metabolism; Calcium Channels - metabolism; Cell Degranulation - drug effects; Cell Line; Cell Membrane - drug effects; Cytoplasm - drug effects; Cytoplasm - metabolism; Humans; Hydrogen-Ion Concentration; Mast Cells - drug effects; Mast Cells - metabolism; Membrane Potentials - drug effects; Mitochondrial Swelling - drug effects; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; Triclosan - toxicity; Super-resolution microscopy; Genetically encoded voltage indicator; Store-operated calcium entry; T cell; Acidification; Mast cell; Triclosan
• ISSN: 1096-0333

Triclosan (TCS) is an antimicrobial agent that was effectively banned by the FDA from hand soaps in 2016, hospital soaps in 2017, and hand sanitizers in 2019; however, TCS can still be found in a few products. At consumer-relevant, non-cytotoxic doses, TCS inhibits the functions of both mitochondria and mast cells, a ubiquitous cell type. Via the store-operated Ca entry mechanism utilized by many immune cells, mast cells undergo antigen-stimulated Ca influx into the cytosol, for proper function. Previous work showed that TCS inhibits Ca dynamics in mast cells, and here we show that TCS also inhibits Ca mobilization in human Jurkat T cells. However, the biochemical mechanism behind the Ca dampening has yet to be elucidated. Three-dimensional super-resolution microscopy reveals that TCS induces mitochondrial swelling, in line with and extending the previous finding of TCS inhibition of mitochondrial membrane potential via its proton ionophoric activity. Inhibition of plasma membrane potential (PMP) by the canonical depolarizer gramicidin can inhibit mast cell function. However, use of the genetically encoded voltage indicators (GEVIs) ArcLight (pH-sensitive) and ASAP2 (pH-insensitive), indicates that TCS does not disrupt PMP. In conjunction with data from a plasma membrane-localized, pH-sensitive reporter, these results indicate that TCS, instead, induces cytosolic acidification in mast cells and T cells. Acidification of the cytosol likely inhibits Ca influx by uncoupling the STIM1/ORAI1 interaction that is required for opening of plasma membrane Ca channels. These results provide a mechanistic explanation of TCS disruption of Ca influx and, thus, of immune cell function.