Topical Application of the Antimicrobial Agent Triclosan Induces NLRP3 Inflammasome Activation and Mitochondrial Dysfunction

Abstract

5-Chloro-2-(2,4-dichlorophenoxy)phenol (triclosan) is an antimicrobial chemical widely used in consumer household and clinical healthcare products. Human and animal studies have associated triclosan exposure with allergic disease. Mechanistic studies have identified triclosan as a mitochondrial uncoupler; recent studies suggest that mitochondria play an important role in immune cell function and are involved in activation of the NLRP3 inflammasome. In this study, early immunological effects were evaluated via NLRP3 activation following dermal triclosan application in a BALB/c murine model. These investigations revealed rapid caspase-1 activation and mature IL-1β secretion in the skin and draining lymph nodes (dLNs) after 1.5% and 3% triclosan exposure. Correspondingly, pro-Il-1b and S100a8 gene expression increased along with extracellular ATP in the skin. Peak gene expression of chemokines associated with caspase-1 activation occurred after 2 days of exposure in both skin tissue and dLNs. Phenotypic analysis showed an increase in neutrophils and macrophages in the dLN and myeloid and inflammatory monocytes in the skin tissue. Triclosan also caused mitochondrial dysfunction shown through effects on mitochondrial reactive oxygen species, mass, mitochondrial membrane potential, and mitochondrial morphology. These results indicate that following triclosan exposure, activation of the NLRP3 inflammasome occurs in both the skin tissue and dLNs, providing a possible mechanism for triclosan’s effects on allergic disease and further support a connection between mitochondrial involvements in immunological responses.

Mitochondria-affecting small molecules ameliorate proteostasis defects associated with neurodegenerative diseases

“…PS103, commonly known as triclosan or irgasan, has been linked to a variety of mitochondrial dysfunctions, including uncoupling of the mitochondrial membrane potential by reversible protonation of the compound’s phenoxy group 71 – 73 and inhibition of Complex II of the ETC 74 . Triclosan has also been associated with increased mitochondrial ROS, reduced mitochondrial mass, and disruptions in mitochondrial morphology 75 . The ability of triclosan to cause several types of mitochondrial damage, apparently with different proximal factors 74 , somewhat reduces its value as a therapeutic agent.…”

Small Molecule Stabilization of PINK-1/PINK1 Improves Neurodegenerative Disease

“…PS103, commonly known as triclosan or irgasan, has been linked with a variety of mitochondrial dysfunction, including uncoupling of the mitochondrial membrane potential by reversible protonation of the phenoxy group (69-71) and inhibition of Complex II of the ETC (72). Triclosan has also been associated with increased mitochondrial ROS, reduced mitochondrial mass, and disruptions in mitochondrial morphology (73). The ability of triclosan to cause several types of mitochondrial damage, apparently with different proximal factors (72), somewhat reduces its value as a therapeutic agent.…”

Mechanism of action of triclosan as an endocrine-disrupting chemical with its impact on human health – literature review

“…Due to the widespread use of the antimicrobial TCS in consumer goods and its metabolites in the environment, TCS as a small chemical can be consumed and absorbed by humans through the skin and mucous membranes [16,17]. The substance can stimulate toll-like receptors (TLR), influence the skin microbiome, and may increase the risk of allergic diseases [16,18]. In a recent in vivo study on female BALB/cAnNTac (BALB/c) mice cells, Weatherly et al reported that proallergic activity is also possible by NLRP3 inflammasome activation, which can be caused by danger-associated molecular patterns (DAMPs), such as S100A8/A9 protein.…”

“…TCS increased S100A8/A9 gene expression in the skin and in draining lymph nodes (dLNS). Interestingly, increased levels of S100A8/A9 and thymic stromal lymphopoietin (TSLP) resulted in exacerbating allergic reaction to ovalbumin in a mouse asthma model [18]. Furthermore, TCS-induced inflammasome activation led to chemokine release -Cxcl1/2, Ccl2, and Ccl19 in the dLN and Cxcl1/2 in the skin, as well as IL-1β release and dysfunction of mitochondria, confirmed by their altered morphology, decrease in mtMass and mitochondrial membrane potential (MMP).…”

“…In the mice model, TCS led to activation of the NLRP3 inflammasome by another pathway -increasing Drp1 and decreasing Opa1 expression [19]. The dynamin-related protein 1 (Drp 1) is associated with mitochondrial fission and the role of optic atrophy 1 (Opa1) is maintenance of the structure of the inner mitochondrial membrane [18].…”