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Collagen VI regulates peripheral nerve regeneration by modulating macrophage recruitment and polarization

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Abstract

Macrophages contribute to peripheral nerve regeneration and produce collagen VI, an extracellular matrix protein involved in nerve function. Here, we show that collagen VI is critical for macrophage migration and polarization during peripheral nerve regeneration. Nerve injury induces a robust upregulation of collagen VI, whereas lack of collagen VI in Col6a1 −/− mice delays peripheral nerve regeneration. In vitro studies demonstrated that collagen VI promotes macrophage migration and polarization via AKT and PKA pathways. Col6a1 −/− macrophages exhibit impaired migration abilities and reduced antiinflammatory (M2) phenotype polarization, but are prone to skewing toward the proinflammatory (M1) phenotype. In vivo, macrophage recruitment and M2 polarization are impaired in Col6a1 −/− mice after nerve injury. The delayed nerve regeneration of Col6a1 −/− mice is induced by macrophage deficits and rejuvenated by transplantation of wild-type bone marrow cells. These results identify collagen VI as a novel regulator for peripheral nerve regeneration by modulating macrophage function.

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Acknowledgments

We are grateful to W. Giuriati for technical assistance, P. Braghetta for helping with mice and R. Wagener for providing α3(VI) collagen antibodies. This work was supported by grants from the Telethon Foundation (GGP10225 and GGP11082), the Italian Ministry of Education, University and Research (RBAP11Z3YA_003), and the University of Padua Strategic Projects. P. Chen is supported by a fellowship from the Cariparo Foundation and an ImmunoTools award providing the cytokines used in this study.

Conflict of interest

The authors declare no potential conflicts of interest.

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Authors and Affiliations

  1. Department of Molecular Medicine, University of Padua, Via Ugo Bassi 58/B, 35131, Padua, Italy

    Peiwen Chen, Matilde Cescon & Paolo Bonaldo

  2. Department of Surgery Oncology and Gastroenterology, University of Padua, 35128, Padua, Italy

    Gaia Zuccolotto

  3. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Mother and Child Sciences, University of Genoa, 16132, Genoa, Italy

    Lucilla Nobbio

  4. Department of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132, Milan, Italy

    Cristina Colombelli & M. Laura Feltri

  5. Section of Pharmacology, Department of Biomedical, Metabolic Sciences and Neurosciences, University of Modena and Reggio Emilia, 41125, Modena, Italy

    Monica Filaferro

  6. Section of Pharmacology, Department of Life Sciences, University of Modena and Reggio Emilia, 41125, Modena, Italy

    Giovanni Vitale

  7. Hunter James Kelly Research Institute, University at Buffalo, State University of New York, New York, NY, 14203, USA

    M. Laura Feltri

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  1. Peiwen Chen
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Correspondence to Paolo Bonaldo.

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Chen, P., Cescon, M., Zuccolotto, G. et al. Collagen VI regulates peripheral nerve regeneration by modulating macrophage recruitment and polarization. Acta Neuropathol 129, 97–113 (2015). https://doi.org/10.1007/s00401-014-1369-9

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  • DOI: https://doi.org/10.1007/s00401-014-1369-9

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