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Pattern of cardiotoxin-induced muscle remodeling in distinct TLR-4 deficient mouse strains

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Abstract

Tissue damage triggers innate immune response mediated by Toll-like receptor 4 (TLR) that recognizes endogenous host danger molecules associated with cell death and tissue inflammation, although the precise role of TLR-4 signaling in muscle tissue repair is still uncertain. Previously, we observed that TLR-4 exerted a protective effect preventing excessive muscular damage induced by Bothrops jararacussu crude venom. This study aimed to evaluate the involvement of TLR-4 at early stages of muscular tissue remodeling in distinct mouse strains after injection of purified snake venom. Muscular injury was induced by injection of 25 µl (0.05 mg/ml) of cardiotoxin (CTX) from Naja mossambica in the gastrocnemius muscle of C3H/HeN (wild-type); C3H/HeJ mice that express a non-functional TLR-4 receptor, C57BL/6 and Tlr4 −/− (B6 background) mice. Comparing to control, Tlr4 −/− mice presented at early stages (3 DPI) of muscle injury mild inflammation with low MMP-9 activity, scarce macrophage infiltration and premature change to anti-inflammatory phenotype, low TNF-α mRNA levels and reduced myogenin expression, with low regeneration and tissue remodeling. The presence of more Ly6Cneg macrophages in Tlr4 −/− mice at 3 DPI indicates that TLR-4 may influence the differentiation into Ly6Cneg or likely affect proliferation of such cells in the muscle. The present study shows that TLR-4 deficiency and genetic background influence the outcome of muscular tissue repair in aseptic lesions and yet still maintaining some level of signaling in the TLR4-mutant mice.

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Acknowledgements

We are grateful to Nina Cortez and Bartira Davi for technical assistance. Financial support from FAPERJ (Fundação de Amparo a Pesquisa do Rio de Janeiro, E-26.111/459/2013) and PROPPI (UFF). EPO was supported by fellowship from CAPES (Brazil) and RFS by a fellowship from REUNI Program (Brazil).

Author contributions

JML-C contributed to the conception of the idea, in the drafting and intellectual content of the manuscript; and in the decision to submit for publication. EPO, RFS contributed to the literature search, experimental procedures. MB and TQ-S contributed to critical evaluation of intellectual content, and editing the manuscript. All authors reviewed and accepted the final version of the manuscript.

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Authors and Affiliations

  1. Department of Immunobiology, Institute of Biology, Fluminense Federal University, Niterói, Rio de Janeiro, 24 020 141, Brazil

    Eustáquio Luiz Paiva-Oliveira, Rafael Ferreira da Silva & Jussara Lagrota-Candido

  2. Department of Cellular and Molecular Biology, Institute of Biology, Fluminense Federal University, Niterói, Rio de Janeiro, Brazil

    Eustáquio Luiz Paiva-Oliveira, Rafael Ferreira da Silva & Thereza Quirico-Santos

  3. Institute of Microbiology, Rio de Janeiro Federal University, Rio de Janeiro, Brazil

    Maria Bellio

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  1. Eustáquio Luiz Paiva-Oliveira
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  2. Rafael Ferreira da Silva
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  3. Maria Bellio
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  4. Thereza Quirico-Santos
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  5. Jussara Lagrota-Candido
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Correspondence to Jussara Lagrota-Candido.

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Paiva-Oliveira, E.L., da Silva, R.F., Bellio, M. et al. Pattern of cardiotoxin-induced muscle remodeling in distinct TLR-4 deficient mouse strains. Histochem Cell Biol 148, 49–60 (2017). https://doi.org/10.1007/s00418-017-1556-6

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