title: Ethylmercury and Hg2+ induce the formation of neutrophil extracellular traps (NETs) by human neutrophil granulocytes.
abstract: Humans are exposed to different mercurial compounds from various sources, most frequently from dental fillings, preservatives in vaccines, or consumption of fish. Among other toxic effects, these substances interact with the immune system. In high doses, mercurials are immunosuppressive. However, lower doses of some mercurials stimulate the immune system, inducing different forms of autoimmunity, autoantibodies, and glomerulonephritis in rodents. Furthermore, some studies suggest a connection between mercury exposure and the occurrence of autoantibodies against nuclear components and granulocyte cytoplasmic proteins in humans. Still, the underlying mechanisms need to be clarified. The present study investigates the formation of neutrophil extracellular traps (NETs) in response to thimerosal and its metabolites ethyl mercury (EtHg), thiosalicylic acid, and mercuric ions (Hg(2+)). Only EtHg and Hg(2+) triggered NETosis. It was independent of PKC, ERK1/2, p38, and zinc signals and not affected by the NADPH oxidase inhibitor DPI. Instead, EtHg and Hg(2+) triggered NADPH oxidase-independent production of ROS, which are likely to be involved in mercurial-induced NET formation. This finding might help understanding the autoimmune potential of mercurial compounds. Some diseases, to which a connection with mercurials has been shown, such as Wegener's granulomatosis and systemic lupus erythematosus, are characterized by high prevalence of autoantibodies against neutrophil-specific auto-antigens. Externalization in the form of NETs may be a source for exposure to these self-antigens. In genetically susceptible individuals, this could be one step in the series of events leading to autoimmunity.
authors.affiliation: Department of Food Chemistry and Toxicology, Berlin Institute of Technology, Gustav-Meyer-Allee 25, 13355, Berlin, Germany. haase@tu-berlin.de.|Medical Faculty, Institute of Immunology, RWTH Aachen University Hospital, Pauwelsstrasse 30, 52074, Aachen, Germany. haase@tu-berlin.de.
authors.forename: Hajo
authors.initials: H
authors.lastname: Haase
authors.affiliation: Medical Faculty, Institute of Immunology, RWTH Aachen University Hospital, Pauwelsstrasse 30, 52074, Aachen, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Hebel
authors.affiliation: Medical Faculty, Institute of Immunology, RWTH Aachen University Hospital, Pauwelsstrasse 30, 52074, Aachen, Germany.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Engelhardt
authors.affiliation: Medical Faculty, Institute of Immunology, RWTH Aachen University Hospital, Pauwelsstrasse 30, 52074, Aachen, Germany. LRink@ukaachen.de.
authors.forename: Lothar
authors.initials: L
authors.lastname: Rink
mesh_terms: D002478:Cells, Cultured; D005035:Ethylmercury Compounds / Q000633:toxicity*; D065206:Extracellular Traps / Q000187:drug effects*; D006098:Granulocytes / Q000187:drug effects; D006801:Humans; D007962:Leukocytes / Q000187:drug effects; D008628:Mercury / Q000633:toxicity*; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012459:Salicylates / Q000633:toxicity; D013438:Sulfhydryl Compounds / Q000633:toxicity; D013849:Thimerosal / Q000633:toxicity; D015032:Zinc / Q000378:metabolism
chemical_list: D005035:Ethylmercury Compounds; D017382:Reactive Oxygen Species; D012459:Salicylates; D013438:Sulfhydryl Compounds; D013849:Thimerosal; C441201:thiosalicylic acid; D019255:NADPH Oxidases; D011494:Protein Kinases; D008628:Mercury; D015032:Zinc
keywords: Autoimmunity; Ethylmercury; Granulocytes; Mercurials; Neutrophil extracellular traps; PMN