Advertisement

Acta Neuropathologica

, Volume 129, Issue 1, pp 97–113 | Cite as

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

  • Peiwen Chen
  • Matilde Cescon
  • Gaia Zuccolotto
  • Lucilla Nobbio
  • Cristina Colombelli
  • Monica Filaferro
  • Giovanni Vitale
  • M. Laura Feltri
  • Paolo Bonaldo
Original Paper

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.

Keywords

Collagen VI Nerve regeneration Macrophage Migration Polarization Peripheral nerve 

Notes

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.

Supplementary material

401_2014_1369_MOESM1_ESM.doc (62 kb)
Supplementary material 1 (DOC 62 kb)
401_2014_1369_MOESM2_ESM.tif (2.5 mb)
Supplementary material 2 (TIFF 2588 kb)
401_2014_1369_MOESM3_ESM.tif (8.3 mb)
Supplementary material 3 (TIFF 8539 kb)
401_2014_1369_MOESM4_ESM.tif (542 kb)
Supplementary material 4 (TIFF 541 kb)
401_2014_1369_MOESM5_ESM.tif (245 kb)
Supplementary material 5 (TIFF 245 kb)
401_2014_1369_MOESM6_ESM.tif (915 kb)
Supplementary material 6 (TIFF 915 kb)
401_2014_1369_MOESM7_ESM.tif (1.9 mb)
Supplementary material 7 (TIFF 1959 kb)
401_2014_1369_MOESM8_ESM.tif (735 kb)
Supplementary material 8 (TIFF 734 kb)
401_2014_1369_MOESM9_ESM.tif (2.4 mb)
Supplementary material 9 (TIFF 2482 kb)

References

  1. 1.
    Aznavoorian S, Stracke ML, Krutzsch H et al (1990) Signal transduction for chemotaxis and haptotaxis by matrix molecules in tumor cells. J Cell Biol 10:1427–1438CrossRefGoogle Scholar
  2. 2.
    Bonaldo P, Braghetta P, Zanetti M et al (1998) Collagen VI deficiency induces early onset myopathy in the mouse: an animal model for Bethlem myopathy. Hum Mol Genet 7:2135–2140PubMedCrossRefGoogle Scholar
  3. 3.
    Byles V, Covarrubias AJ, Ben-Sahra I et al (2013) The TSC-mTOR pathway regulates macrophage polarization. Nat Commun 4:2834PubMedCrossRefGoogle Scholar
  4. 4.
    Chen P, Bonaldo P (2013) Role of macrophage polarization in tumor angiogenesis and vessel normalization: implications for new anticancer therapies. Int Rev Cell Mol Biol 301:1–35PubMedCrossRefGoogle Scholar
  5. 5.
    Chen P, Cescon M, Bonaldo P (2013) Collagen VI in cancer and its biological mechanisms. Trends Mol Med 19:410–417PubMedCrossRefGoogle Scholar
  6. 6.
    Chen P, Cescon M, Bonaldo P (2014) Autophagy-mediated regulation of macrophages and its applications for cancer. Autophagy 10:192–200PubMedCrossRefGoogle Scholar
  7. 7.
    Chen P, Cescon M, Megighian A, Bonaldo P (2014) Collagen VI regulates peripheral nerve myelination and function. FASEB J 28:1145–1156PubMedCrossRefGoogle Scholar
  8. 8.
    Chen P, Huang Y, Bong R et al (2011) Tumor-associated macrophages promote angiogenesis and melanoma growth via adrenomedullin in a paracrine and autocrine manner. Clin Cancer Res 17:7230–7239PubMedCrossRefGoogle Scholar
  9. 9.
    Christie KJ, Webber CA, Martinez JA et al (2010) PTEN inhibition to facilitate intrinsic regenerative outgrowth of adult peripheral axons. J Neurosci 30:9306–9315PubMedCrossRefGoogle Scholar
  10. 10.
    Cote SC, Pasvanis S, Bounou S, Dumais N (2009) CCR7-specific migration to CCL19 and CCL21 is induced by PGE(2) stimulation in human monocytes: involvement of EP(2)/EP(4) receptors activation. Mol Immunol 46:2682–2693PubMedCrossRefGoogle Scholar
  11. 11.
    Diaz-Munoz MD, Osma-Garcia IC, Iniguez MA, Fresno M (2013) Cyclooxygenase-2 deficiency in macrophages leads to defective p110gamma PI3K signaling and impairs cell adhesion and migration. J Immunol 191:395–406PubMedCrossRefGoogle Scholar
  12. 12.
    Du R, Lu KV, Petritsch C et al (2008) HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13:206–220PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Dubovy P, Jancalek R, Kubek T (2013) Role of inflammation and cytokines in peripheral nerve regeneration. Int Rev Neurobiol 108:173–206PubMedCrossRefGoogle Scholar
  14. 14.
    Farah MH, Pan BH, Hoffman PN et al (2011) Reduced BACE1 activity enhances clearance of myelin debris and regeneration of axons in the injured peripheral nervous system. J Neurosci 31:5744–5754PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Gara SK, Grumati P, Squarzoni S et al (2011) Differential and restricted expression of novel collagen VI chains in mouse. Matrix Biol 30:248–257PubMedCrossRefGoogle Scholar
  16. 16.
    Germano G, Frapolli R, Belgiovine C et al (2013) Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell 23:249–262PubMedCrossRefGoogle Scholar
  17. 17.
    Ghosh-Roy A, Wu Z, Goncharov A et al (2010) Calcium and cyclic AMP promote axonal regeneration in Caenorhabditis elegans and require DLK-1 kinase. J Neurosci 30:3175–3183PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Gordon S, Martinez FO (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32:593–604PubMedCrossRefGoogle Scholar
  19. 19.
    Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964PubMedCrossRefGoogle Scholar
  20. 20.
    Griffin JW, George R, Ho T (1993) Macrophage systems in peripheral nerves. A review. J Neuropathol Exp Neurol 52:553–560PubMedCrossRefGoogle Scholar
  21. 21.
    Horie H, Kadoya T, Hikawa N et al (2004) Oxidized galectin-1 stimulates macrophages to promote axonal regeneration in peripheral nerves after axotomy. J Neurosci 24:1873–1880PubMedCrossRefGoogle Scholar
  22. 22.
    Inserra MM, Bloch DA, Terris DJ (1998) Functional indices for sciatic, peroneal, and posterior tibial nerve lesions in the mouse. Microsurgery 18:119–124PubMedCrossRefGoogle Scholar
  23. 23.
    Irwin WA, Bergamin N, Sabatelli P et al (2003) Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency. Nat Genet 35:367–371PubMedCrossRefGoogle Scholar
  24. 24.
    Klominek J, Robért KH, Sundqvist KG (1993) Chemotaxis and haptotaxis of human malignant mesothelioma cells: effects of fibronectin, laminin, type IV collagen, and an autocrine motility factor-like substance. Cancer Res 53:4376–4382PubMedGoogle Scholar
  25. 25.
    Liao X, Sharma N, Kapadia F et al (2011) Kruppel-like factor 4 regulates macrophage polarization. J Clin Invest 121:2736–2749PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    López-Vales R, Navarro X, Shimizu T et al (2008) Intracellular phospholipase A(2) group IVA and group VIA play important roles in Wallerian degeneration and axon regeneration after peripheral nerve injury. Brain 131:2620–2631PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Ma L, Dong F, Zaid M et al (2012) ABCA1 protein enhances toll-like receptor 4 (TLR4)-stimulated interleukin-10 (IL-10) secretion through protein kinase A (PKA) activation. J Biol Chem 287:40502–40512PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Ma Y, Halade GV, Zhang J et al (2013) Matrix metalloproteinase-28 deletion exacerbates cardiac dysfunction and rupture after myocardial infarction in mice by inhibiting M2 macrophage activation. Circ Res 112:675–688PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Mantovani A, Biswas SK, Galdiero MR et al (2013) Macrophage plasticity and polarization in tissue repair and remodeling. J Pathol 229:176–185PubMedCrossRefGoogle Scholar
  30. 30.
    Mokarram N, Merchant A, Mukhatyar V et al (2012) Effect of modulating macrophage phenotype on peripheral nerve repair. Biomaterials 33:8793–8801PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8:958–969PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Mueller M, Leonhard C, Wacker K et al (2003) Macrophage response to peripheral nerve injury: the quantitative contribution of resident and hematogenous macrophages. Lab Invest 83:175–185PubMedCrossRefGoogle Scholar
  33. 33.
    Namikawa K, Okamoto T, Suzuki A et al (2006) Pancreatitis-associated protein-III is a novel macrophage chemoattractant implicated in nerve regeneration. J Neurosci 26:7460–7467PubMedCrossRefGoogle Scholar
  34. 34.
    Niemi JP, DeFrancesco-Lisowitz A, Roldán-Hernández L et al (2013) A critical role for macrophages near axotomized neuronal cell bodies in stimulating nerve regeneration. J Neurosci 33:16236–16248PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Parrinello S, Napoli I, Ribeiro S et al (2010) EphB signaling directs peripheral nerve regeneration through Sox2-dependent Schwann cell sorting. Cell 143:145–155PubMedCrossRefGoogle Scholar
  36. 36.
    Perrin FE, Lacroix S, viles-Trigueros M, David S (2005) Involvement of monocyte chemoattractant protein-1, macrophage inflammatory protein-1alpha and interleukin-1beta in Wallerian degeneration. Brain 128:854–866PubMedCrossRefGoogle Scholar
  37. 37.
    Ploeger DT, van Putten SM, Koerts JA et al (2012) Human macrophages primed with angiogenic factors show dynamic plasticity, irrespective of extracellular matrix components. Immunobiology 217:299–306PubMedCrossRefGoogle Scholar
  38. 38.
    Santos-Sierra S, Deshmukh SD, Kalnitski J et al (2009) Mal connects TLR2 to PI3Kinase activation and phagocyte polarization. EMBO J 28:2018–2027PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Schafer M, Fruttiger M, Montag D et al (1996) Disruption of the gene for the myelin-associated glycoprotein improves axonal regrowth along myelin in C57BL/Wlds mice. Neuron 16:1107–1113PubMedCrossRefGoogle Scholar
  40. 40.
    Schnoor M, Cullen P, Lorkowski J et al (2008) Production of type VI collagen by human macrophages: a new dimension in macrophage functional heterogeneity. J Immunol 180:5707–5719PubMedCrossRefGoogle Scholar
  41. 41.
    Shamash S, Reichert F, Rotshenker S (2002) The cytokine network of Wallerian degeneration: tumor necrosis factor-alpha, interleukin-1alpha, and interleukin-1beta. J Neurosci 22:3052–3060PubMedGoogle Scholar
  42. 42.
    Sicari BM, Johnson SA, Siu BF et al (2012) The effect of source animal age upon the in vivo remodeling characteristics of an extracellular matrix scaffold. Biomaterials 33:5524–5533PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Siconolfi LB, Seeds NW (2001) Mice lacking tPA, uPA, or plasminogen genes showed delayed functional recovery after sciatic nerve crush. J Neurosci 21:4348–4355PubMedGoogle Scholar
  44. 44.
    Spencer M, Yao-Borengasser A, Unal R et al (2010) Adipose tissue macrophages in insulin-resistant subjects are associated with collagen VI and fibrosis and demonstrate alternative activation. Am J Physiol Endocrinol Metab 299:E1016–E1027PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Tofaris GK, Patterson PH, Jessen KR, Mirsky R (2002) Denervated Schwann cells attract macrophages by secretion of leukemia inhibitory factor (LIF) and monocyte chemoattractant protein-1 in a process regulated by interleukin-6 and LIF. J Neurosci 22:6696–6703PubMedGoogle Scholar
  46. 46.
    Urciuolo A, Quarta M, Morbidoni V et al (2013) Collagen VI regulates satellite cell self-renewal and muscle regeneration. Nat Commun 4:1964PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Vargas ME, Watanabe J, Singh SJ et al (2010) Endogenous antibodies promote rapid myelin clearance and effective axon regeneration after nerve injury. Proc Natl Acad Sci 107:11993–11998PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Vitale P, Braghetta P, Volpin D et al (2001) Mechanisms of transcriptional activation of the col6a1 gene during Schwann cell differentiation. Mech Dev 102:145–156PubMedCrossRefGoogle Scholar
  49. 49.
    Wang AZ, Chen JM, Fisher GW et al (1994) Improved in vitro models for assay of rheumatoid synoviocyte chemotaxis. Clin Exp Rheumatol 12:293–299PubMedGoogle Scholar
  50. 50.
    Ydens E, Cauwels A, Asselbergh B et al (2012) Acute injury in the peripheral nervous system triggers an alternative macrophage response. J Neuroinflammation 9:176PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Zhang L, Johnson D, Johnson JA (2013) Deletion of Nrf2 impairs functional recovery, reduces clearance of myelin debris and decreases axonal remyelination after peripheral nerve injury. Neurobiol Dis 54:329–338PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Zhu X, Lee JY, Timmins JM et al (2008) Increased cellular free cholesterol in macrophage-specific Abca1 knock-out mice enhances pro-inflammatory response of macrophages. J Biol Chem 283:22930–22941PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Peiwen Chen
    • 1
  • Matilde Cescon
    • 1
  • Gaia Zuccolotto
    • 2
  • Lucilla Nobbio
    • 3
  • Cristina Colombelli
    • 4
  • Monica Filaferro
    • 5
  • Giovanni Vitale
    • 6
  • M. Laura Feltri
    • 4
    • 7
  • Paolo Bonaldo
    • 1
  1. 1.Department of Molecular MedicineUniversity of PaduaPaduaItaly
  2. 2.Department of Surgery Oncology and GastroenterologyUniversity of PaduaPaduaItaly
  3. 3.Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Mother and Child SciencesUniversity of GenoaGenoaItaly
  4. 4.Department of Genetics and Cell BiologySan Raffaele Scientific InstituteMilanItaly
  5. 5.Section of Pharmacology, Department of Biomedical, Metabolic Sciences and NeurosciencesUniversity of Modena and Reggio EmiliaModenaItaly
  6. 6.Section of Pharmacology, Department of Life SciencesUniversity of Modena and Reggio EmiliaModenaItaly
  7. 7.Hunter James Kelly Research InstituteUniversity at Buffalo, State University of New YorkNew YorkUSA

Personalised recommendations