title: Methionine and methionine sulfoxide treatment induces M1/classical macrophage polarization and modulates oxidative stress and purinergic signaling parameters.
abstract: Methionine is an essential amino acid involved in critical metabolic process, and regulation of methionine flux through metabolism is important to supply this amino acid for cell needs. Elevation in plasma methionine commonly occurs due to mutations in methionine-metabolizing enzymes, such as methionine adenosyltransferase. Hypermethioninemic patients exhibit clinical manifestations, including neuronal and liver disorders involving inflammation and tissue injury, which pathophysiology is not completely established. Here, we hypothesize that alterations in macrophage inflammatory response may contribute to deleterious effects of hypermethioninemia. To this end, macrophage primary cultures were exposed to methionine (1 mM) and/or its metabolite methionine sulfoxide (0.5 mM), and M1/proinflammatory or M2/anti-inflammatory macrophage polarization was evaluated. In addition, inflammation-related pathways including oxidative stress parameters, as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities; reactive oxygen species (ROS) production, and purinergic signaling, as ATP/ADP/AMPase activities, were investigated. Methionine and/or methionine sulfoxide induced M1/classical macrophage activation, which is related to proinflammatory responses characterized by increased iNOS activity and TNF-α release. Further experiments showed that treatments promoted alterations on redox state of macrophages by differentially modulated SOD and CAT activities and ROS levels. Finally, methionine and/or methionine sulfoxide treatment also altered the extracellular nucleotide metabolism, promoting an increase of ATPase/ADPase activities in macrophages. In conclusion, these findings contribute to better understand the participation of proinflammatory responses in cell injury observed in hypermethioninemic patients.
authors.affiliation: Laboratório de Neuroquímica, Inflamação e Câncer, Centro de Ciências Químicas Farmacêuticas e de Alimentos, Universidade Federal de Pelotas (UFPel), Pelotas, RS, Brazil.
authors.forename: Lien M
authors.initials: LM
authors.lastname: Dos Santos
authors.affiliation: Laboratório de Biomarcadores, Centro de Ciências Químicas Farmacêuticas e de Alimentos, Universidade Federal de Pelotas (UFPel), Campus Universitário s/n, Capão do Leão, Pelotas, RS, 96160-000, Brazil.
authors.forename: Tatiane M
authors.initials: TM
authors.lastname: da Silva
authors.affiliation: Laboratório de Neuroquímica, Inflamação e Câncer, Centro de Ciências Químicas Farmacêuticas e de Alimentos, Universidade Federal de Pelotas (UFPel), Pelotas, RS, Brazil.|Departamento de Ciências Básicas da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Rua Sarmento Leite, 245 - Anexo I - sala 303, Porto Alegre, RS, 90050-170, Brazil.
authors.forename: Juliana H
authors.initials: JH
authors.lastname: Azambuja
authors.affiliation: Laboratório de Neuroquímica, Inflamação e Câncer, Centro de Ciências Químicas Farmacêuticas e de Alimentos, Universidade Federal de Pelotas (UFPel), Pelotas, RS, Brazil.
authors.forename: Priscila T
authors.initials: PT
authors.lastname: Ramos
authors.affiliation: Laboratório de Biomarcadores, Centro de Ciências Químicas Farmacêuticas e de Alimentos, Universidade Federal de Pelotas (UFPel), Campus Universitário s/n, Capão do Leão, Pelotas, RS, 96160-000, Brazil.
authors.forename: Pathise S
authors.initials: PS
authors.lastname: Oliveira
authors.affiliation: Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Rio Grande (FURG), Rio Grande, RS, Brazil.
authors.forename: Elita F
authors.initials: EF
authors.lastname: da Silveira
authors.affiliation: Laboratório de Neuroquímica, Inflamação e Câncer, Centro de Ciências Químicas Farmacêuticas e de Alimentos, Universidade Federal de Pelotas (UFPel), Pelotas, RS, Brazil.
authors.forename: Nathalia S
authors.initials: NS
authors.lastname: Pedra
authors.affiliation: Laboratório de Neuroquímica, Inflamação e Câncer, Centro de Ciências Químicas Farmacêuticas e de Alimentos, Universidade Federal de Pelotas (UFPel), Pelotas, RS, Brazil.
authors.forename: Kennia
authors.initials: K
authors.lastname: Galdino
authors.affiliation: Laboratório de Neuroquímica, Inflamação e Câncer, Centro de Ciências Químicas Farmacêuticas e de Alimentos, Universidade Federal de Pelotas (UFPel), Pelotas, RS, Brazil.
authors.forename: Carlus A T
authors.initials: CA
authors.lastname: do Couto
authors.affiliation: Laboratório de Neuroquímica, Inflamação e Câncer, Centro de Ciências Químicas Farmacêuticas e de Alimentos, Universidade Federal de Pelotas (UFPel), Pelotas, RS, Brazil.
authors.forename: Mayara S P
authors.initials: MS
authors.lastname: Soares
authors.affiliation: Laboratório de Biomarcadores, Centro de Ciências Químicas Farmacêuticas e de Alimentos, Universidade Federal de Pelotas (UFPel), Campus Universitário s/n, Capão do Leão, Pelotas, RS, 96160-000, Brazil.
authors.forename: Rejane G
authors.initials: RG
authors.lastname: Tavares
authors.affiliation: Laboratório de Neuroquímica, Inflamação e Câncer, Centro de Ciências Químicas Farmacêuticas e de Alimentos, Universidade Federal de Pelotas (UFPel), Pelotas, RS, Brazil.
authors.forename: Roselia M
authors.initials: RM
authors.lastname: Spanevello
authors.affiliation: Laboratório de Biomarcadores, Centro de Ciências Químicas Farmacêuticas e de Alimentos, Universidade Federal de Pelotas (UFPel), Campus Universitário s/n, Capão do Leão, Pelotas, RS, 96160-000, Brazil. fmstefanello@gmail.com.
authors.forename: Francieli M
authors.initials: FM
authors.lastname: Stefanello
authors.affiliation: Departamento de Ciências Básicas da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Rua Sarmento Leite, 245 - Anexo I - sala 303, Porto Alegre, RS, 90050-170, Brazil. ebraganhol@ufcspa.edu.br.
authors.forename: Elizandra
authors.initials: E
authors.lastname: Braganhol
mesh_terms: D000818:Animals; D002374:Catalase / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008715:Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D008715:Methionine; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; C013111:methionine sulfoxide
keywords: Ectonucleotidases; Macrophage polarization; Methionine; Methionine sulfoxide; Oxidative stress