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Differential Macrophage Subsets in Muscle Damage Induced by a K49-PLA2 from Bothrops jararacussu Venom Modulate the Time Course of the Regeneration Process

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Abstract

Bothrops snakes cause around 80% of snakebites in Brazil, with muscle tissue damage as an important consequence, which may cause dysfunction on the affected limb. Bothropstoxin-I (BthTX-I) from Bothrops jararacussu is a K49-phospholipase A2, involved in the injury and envenomation’s inflammatory response. Immune system components act in the resolution of tissue damage and regeneration. Thus, macrophages exert a crucial role in the elimination of dead tissue and muscle repair. Here, we studied the cellular influx and presence of classical and alternative macrophages (M1 and M2) during muscle injury induced by BthTX-I and the regeneration process. BthTX-I elicited intense inflammatory response characterized by neutrophil migration, then increased influx of M1 macrophages followed by M2 population that declined, resulting in tissue regeneration. The high expressions of TNF-α and IL6 were changed by increased TGF-β expression after BthTX-I injection, coinciding with the iNOs and arginase expression and the peaks of M1 and M2 macrophages in muscle tissue. A coordinated sequence of PAX7, MyoD, and myogenin expression involved in muscle regenerative process appeared after BthTX-I injection. Together, these results demonstrate a direct correlation between the macrophage subsets, cytokine microenvironment, and the myogenesis process. This information may be useful for new envenomation and muscular dysfunction therapies.

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Acknowledgements

Priscila Andrade Ranéia e Silva received a fellowship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). We thank Dr. Jorge M.C. Ferreira-Jr. for his help in flow cytometry.

Funding

This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (311915/2012-4; 309392/2015-2).

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Authors and Affiliations

  1. Immunopathology Laboratory, Butantan Institute, São Paulo, Brazil

    Priscila Andrade Ranéia e Silva, Ana Maria Moura-da-Silva & Eliana L. Faquim-Mauro

  2. Laboratory of Division of Genetics, Butantan Institute, São Paulo, Brazil

    Adriana da Costa Neves

  3. Londrina State University, Paraná, Brazil

    Cristiani Baldo da Rocha

  4. Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil

    Eliana L. Faquim-Mauro

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  1. Priscila Andrade Ranéia e Silva
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Ranéia e Silva, P.A., da Costa Neves, A., da Rocha, C.B. et al. Differential Macrophage Subsets in Muscle Damage Induced by a K49-PLA2 from Bothrops jararacussu Venom Modulate the Time Course of the Regeneration Process. Inflammation 42, 1542–1554 (2019). https://doi.org/10.1007/s10753-019-01016-y

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