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Characterization of macrophage phenotype, redox, and purinergic response upon chronic treatment with methionine and methionine sulfoxide in mice

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Abstract

Hypermethioninemia is a disorder characterized by high plasma levels of methionine (Met) and its metabolites such as methionine sulfoxide (MetO). Studies have reported associated inflammatory complications, but the mechanisms involved in the pathophysiology of hypermethioninemia are still uncertain. The present study aims to evaluate the effect of chronic administration of Met and/or MetO on phenotypic characteristics of macrophages, in addition to oxidative stress, purinergic system, and inflammatory mediators in macrophages. In this study, Swiss male mice were subcutaneously injected with Met and MetO at concentrations of 0.35–1.2 g/kg body weight and 0.09–0.3 g/kg body weight, respectively, from the 10th–38th day post-birth, while the control group was treated with saline solution. The results revealed that Met and/or MetO induce an M1/classical activation phenotype associated with increased levels of tumor necrosis factor alpha and nitrite, and reduced arginase activity. It was also found that Met and/or MetO alter the activity of antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase, as well as the levels of thiol and reactive oxygen species in macrophages. The chronic administration of Met and/or MetO also promotes alteration in the hydrolysis of ATP and ADP, as indicated by the increased activity of ectonucleotidases. These results demonstrate that chronic administration of Met and/or MetO promotes activated pro-inflammatory profile by inducing M1/classical macrophage polarization. Thus, the changes in redox status and purinergic system upon chronic Met and/or MetO exposure may contribute towards better understanding of the alterations consistent with hypermethioninemic patients.

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Acknowledgements

This research was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq—Universal Processo 454262/2014-0) and Fundação de Amparo à Pesquisa do Rio Grande do Sul (FAPERGS). This study was financed in part by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior- Brasil (CAPES)—Finance code 001.

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Authors and Affiliations

  1. Laboratório de Biomarcadores, Centro de Ciências Químicas, Farmacêuticas e de Alimentos (CCQFA), Universidade Federal de Pelotas (UFPel), Campus Universitário s/n, Pelotas, RS, 96160-000, Brasil

    Thaís S. Franceschi, Natália P. Bona & Francieli M. Stefanello

  2. Laboratório de Neuroquímica, Inflamação e Câncer, Centro de Ciências Químicas, Farmacêuticas e de Alimentos (CCQFA), Universidade Federal de Pelotas (UFPel), Pelotas, RS, Brasil

    Mayara S. P. Soares, Nathalia S. Pedra, Luiza Spohr, Fernanda C. Teixeira, Carlus A. T. do Couto & Roselia M. Spanevello

  3. Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil

    Marion Deon & Carmen R. Vargas

  4. Departamento de Ciências Básicas da Saúde (DCBS), Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brasil

    Elizandra Braganhol

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  1. Thaís S. Franceschi
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  2. Mayara S. P. Soares
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Correspondence to Francieli M. Stefanello.

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The authors declare that there are no conflicts of interest.

Ethical approval

All animal procedures were approved by the Ethics Committee of Animal Experimentation from the Federal University of Pelotas (protocol under project number: CEEA 9221-2013). The use of the animals was in accordance with the Brazilian Guidelines for the Care and Use of Animals in Scientific Research Activities (DBCA), National Council of Control of Animal Experimentation (CONCEA) and with the NIH Guide for Care and Use of Laboratory Animals.

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Franceschi, T.S., Soares, M.S.P., Pedra, N.S. et al. Characterization of macrophage phenotype, redox, and purinergic response upon chronic treatment with methionine and methionine sulfoxide in mice. Amino Acids 52, 629–638 (2020). https://doi.org/10.1007/s00726-020-02841-4

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