Skip to main content
Springer Nature Link
Log in

The Contribution of the Extracellular Matrix to the BBB in Steady State and Inflammatory Conditions

  • Chapter
  • First Online:
The Blood Brain Barrier and Inflammation

Part of the book series: Progress in Inflammation Research ((PIR))

Abstract

The delicate neurons in the central nervous system are protected from the circulation by the blood-brain barrier (BBB), which prevents the transmigration of cells and harmful substances from entering the brain. Much attention has focused on the cellular components (endothelial cells and astrocyte endfeet) of this barrier, but it is becoming increasingly obvious that the noncellular components, specifically the basement membranes (BMs), play a crucial role in the integrity of the BBB. Not only do the BMs help to maintain barrier tightness through their actual presence, but also their distinct composition plays an important role in the regulation of their cellular counterparts. In this chapter we will describe the different BMs that are found in the BBB and present findings from an animal model of autoimmunity that have revealed considerable information on the function of the different BMs in maintaining BBB integrity.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Agrawal S, Anderson P, Durbeej M, van Rooijen N, Ivars F, Opdenakker G, Sorokin LM (2006) Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis. J Exp Med 203(4):1007–1019. doi:10.1084/jem.20051342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Alkan A, Sigirci A, Kutlu R, Aslan M, Doganay S, Yakinci C (2007) Merosin-negative congenital muscular dystrophy: diffusion-weighted imaging findings of brain. J Child Neurol 22(5):655–659. doi:10.1177/0883073807303219

    Article  PubMed  Google Scholar 

  3. Armulik A, Genove G, Mae M, Nisancioglu MH, Wallgard E, Niaudet C, He L, Norlin J, Lindblom P, Strittmatter K, Johansson BR, Betsholtz C (2010) Pericytes regulate the blood-brain barrier. Nature 468(7323):557–561. doi:10.1038/nature09522

    Article  CAS  PubMed  Google Scholar 

  4. Bader BL, Rayburn H, Crowley D, Hynes RO (1998) Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha v integrins. Cell 95(4):507–519

    Article  CAS  PubMed  Google Scholar 

  5. Behrens DT, Villone D, Koch M, Brunner G, Sorokin L, Robenek H, Bruckner-Tuderman L, Bruckner P, Hansen U (2012) The epidermal basement membrane is a composite of separate laminin- or collagen IV-containing networks connected by aggregated perlecan, but not by nidogens. J Biol Chem 287(22):18700–18709. doi:10.1074/jbc.M111.336073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bouvard C, De Arcangelis A, Dizier B, Galy-Fauroux I, Fischer AM, Georges-Labouesse E, Helley D (2012) Tie2-dependent knockout of alpha6 integrin subunit in mice reduces post-ischaemic angiogenesis. Cardiovasc Res 95(1):39–47. doi:10.1093/cvr/cvs153

    Article  CAS  PubMed  Google Scholar 

  7. Chen ZL, Yao Y, Norris EH, Kruyer A, Jno-Charles O, Akhmerov A, Strickland S (2013) Ablation of astrocytic laminin impairs vascular smooth muscle cell function and leads to hemorrhagic stroke. J Cell Biol 202(2):381–395. doi:10.1083/jcb.201212032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Daneman R, Zhou L, Kebede AA, Barres BA (2010) Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 468(7323):562–566. doi:10.1038/nature09513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. De Arcangelis A, Mark M, Kreidberg J, Sorokin L, Georges-Labouesse E (1999) Synergistic activities of alpha3 and alpha6 integrins are required during apical ectodermal ridge formation and organogenesis in the mouse. Development 126(17):3957–3968

    PubMed  Google Scholar 

  10. Flanagan K, Fitzgerald K, Baker J, Regnstrom K, Gardai S, Bard F, Mocci S, Seto P, You M, Larochelle C, Prat A, Chow S, Li L, Vandevert C, Zago W, Lorenzana C, Nishioka C, Hoffman J, Botelho R, Willits C, Tanaka K, Johnston J, Yednock T (2012) Laminin-411 is a vascular ligand for MCAM and facilitates TH17 cell entry into the CNS. PLoS One 7(7), e40443. doi:10.1371/journal.pone.0040443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fox JW, Mayer U, Nischt R, Aumailley M, Reinhardt D, Wiedemann H, Mann K, Timpl R, Krieg T, Engel J et al (1991) Recombinant nidogen consists of three globular domains and mediates binding of laminin to collagen type IV. EMBO J 10(11):3137–3146

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Fujiwara H, Kikkawa Y, Sanzen N, Sekiguchi K (2001) Purification and characterization of human laminin-8. Laminin-8 stimulates cell adhesion and migration through alpha3beta1 and alpha6beta1 integrins. J Biol Chem 276(20):17550–17558. doi:10.1074/jbc.M010155200

    Article  CAS  PubMed  Google Scholar 

  13. Gould DB, Phalan FC, Breedveld GJ, van Mil SE, Smith RS, Schimenti JC, Aguglia U, van der Knaap MS, Heutink P, John SW (2005) Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Science 308(5725):1167–1171. doi:10.1126/science.1109418

    Article  CAS  PubMed  Google Scholar 

  14. Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, Bousser MG, Heutink P, Miner JH, Tournier-Lasserve E, John SW (2006) Role of COL4A1 in small-vessel disease and hemorrhagic stroke. N Engl J Med 354(14):1489–1496. doi:10.1056/NEJMoa053727

    Article  CAS  PubMed  Google Scholar 

  15. Hynes RO (1992) Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69(1):11–25

    Article  CAS  PubMed  Google Scholar 

  16. Jeanne M, Jorgensen J, Gould DB (2015) Molecular and Genetic Analyses of Collagen Type IV Mutant Mouse Models of Spontaneous Intracerebral Hemorrhage Identify Mechanisms for Stroke Prevention. Circulation 131(18):1555–1565. doi:10.1161/CIRCULATIONAHA.114.013395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kikkawa Y, Moulson CL, Virtanen I, Miner JH (2002) Identification of the binding site for the Lutheran blood group glycoprotein on laminin alpha 5 through expression of chimeric laminin chains in vivo. J Biol Chem 277(47):44864–44869. doi:10.1074/jbc.M208731200

    Article  CAS  PubMed  Google Scholar 

  18. Kikkawa Y, Sanzen N, Fujiwara H, Sonnenberg A, Sekiguchi K (2000) Integrin binding specificity of laminin-10/11: laminin-10/11 are recognized by alpha 3 beta 1, alpha 6 beta 1 and alpha 6 beta 4 integrins. J Cell Sci 113(Pt 5):869–876

    CAS  PubMed  Google Scholar 

  19. Lau LW, Cua R, Keough MB, Haylock-Jacobs S, Yong VW (2013) Pathophysiology of the brain extracellular matrix: a new target for remyelination. Nat Rev Neurosci 14(10):722–729. doi:10.1038/nrn3550

    Article  CAS  PubMed  Google Scholar 

  20. McCarty JH, Lacy-Hulbert A, Charest A, Bronson RT, Crowley D, Housman D, Savill J, Roes J, Hynes RO (2005) Selective ablation of alphav integrins in the central nervous system leads to cerebral hemorrhage, seizures, axonal degeneration and premature death. Development 132(1):165–176. doi:10.1242/dev.01551

    Article  CAS  PubMed  Google Scholar 

  21. Milner R, Hung S, Erokwu B, Dore-Duffy P, LaManna JC, del Zoppo GJ (2008) Increased expression of fibronectin and the alpha 5 beta 1 integrin in angiogenic cerebral blood vessels of mice subject to hypobaric hypoxia. Mol Cell Neurosci 38(1):43–52. doi:10.1016/j.mcn.2008.01.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Moore SA, Saito F, Chen J, Michele DE, Henry MD, Messing A, Cohn RD, Ross-Barta SE, Westra S, Williamson RA, Hoshi T, Campbell KP (2002) Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy. Nature 418(6896):422–425. doi:10.1038/nature00838

    Article  CAS  PubMed  Google Scholar 

  23. Nicholas DS, Weller RO (1988) The fine anatomy of the human spinal meninges. A light and scanning electron microscopy study. J Neurosurg 69(2):276–282. doi:10.3171/jns.1988.69.2.0276

    Article  CAS  PubMed  Google Scholar 

  24. Noell S, Fallier-Becker P, Deutsch U, Mack AF, Wolburg H (2009) Agrin defines polarized distribution of orthogonal arrays of particles in astrocytes. Cell Tissue Res 337(2):185–195. doi:10.1007/s00441-009-0812-z

    Article  CAS  PubMed  Google Scholar 

  25. Osada T, Gu YH, Kanazawa M, Tsubota Y, Hawkins BT, Spatz M, Milner R, del Zoppo GJ (2011) Interendothelial claudin-5 expression depends on cerebral endothelial cell-matrix adhesion by beta(1)-integrins. J Cereb Blood Flow Metab 31(10):1972–1985. doi:10.1038/jcbfm.2011.99

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Parsons SF, Lee G, Spring FA, Willig TN, Peters LL, Gimm JA, Tanner MJ, Mohandas N, Anstee DJ, Chasis JA (2001) Lutheran blood group glycoprotein and its newly characterized mouse homologue specifically bind alpha5 chain-containing human laminin with high affinity. Blood 97(1):312–320

    Article  CAS  PubMed  Google Scholar 

  27. Ransohoff RM, Engelhardt B (2012) The anatomical and cellular basis of immune surveillance in the central nervous system. Nat Rev Immunol 12(9):623–635. doi:10.1038/nri3265

    Article  CAS  PubMed  Google Scholar 

  28. Rauch U (2007) Brain matrix: structure, turnover and necessity. Biochem Soc Trans 35(Pt 4):656–660. doi:10.1042/BST0350656

    Article  CAS  PubMed  Google Scholar 

  29. Renard D, Mine M, Pipiras E, Labauge P, Delahaye A, Benzacken B, Tournier-Lasserve E (2014) Cerebral small-vessel disease associated with COL4A1 and COL4A2 gene duplications. Neurology 83(11):1029–1031. doi:10.1212/WNL.0000000000000769

    Article  PubMed  Google Scholar 

  30. Sasaki T, Timpl R (2001) Domain IVa of laminin alpha5 chain is cell-adhesive and binds beta1 and alphaVbeta3 integrins through Arg-Gly-Asp. FEBS Lett 509(2):181–185

    Article  CAS  PubMed  Google Scholar 

  31. Sixt M, Engelhardt B, Pausch F, Hallmann R, Wendler O, Sorokin LM (2001) Endothelial cell laminin isoforms, laminins 8 and 10, play decisive roles in T cell recruitment across the blood-brain barrier in experimental autoimmune encephalomyelitis. J Cell Biol 153(5):933–946

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Song J, Wu C, Korpos E, Zhang X, Agrawal SM, Wang Y, Faber C, Schafers M, Korner H, Opdenakker G, Hallmann R, Sorokin L (2015) Focal MMP-2 and MMP-9 activity at the blood-brain barrier promotes chemokine-induced leukocyte migration. Cell Rep 10(7):1040–1054. doi:10.1016/j.celrep.2015.01.037

    Article  CAS  PubMed  Google Scholar 

  33. Sorokin L (2010) The impact of the extracellular matrix on inflammation. Nat Rev Immunol 10(10):712–723. doi:10.1038/nri2852

    Article  CAS  PubMed  Google Scholar 

  34. Sorokin LM, Pausch F, Frieser M, Kroger S, Ohage E, Deutzmann R (1997) Developmental regulation of the laminin alpha5 chain suggests a role in epithelial and endothelial cell maturation. Dev Biol 189(2):285–300. doi:10.1006/dbio.1997.8668

    Article  CAS  PubMed  Google Scholar 

  35. Steiner E, Enzmann GU, Lin S, Ghavampour S, Hannocks MJ, Zuber B, Ruegg MA, Sorokin L, Engelhardt B (2012) Loss of astrocyte polarization upon transient focal brain ischemia as a possible mechanism to counteract early edema formation. Glia 60(11):1646–1659. doi:10.1002/glia.22383

    Article  PubMed  Google Scholar 

  36. Talts JF, Andac Z, Gohring W, Brancaccio A, Timpl R (1999) Binding of the G domains of laminin alpha1 and alpha2 chains and perlecan to heparin, sulfatides, alpha-dystroglycan and several extracellular matrix proteins. EMBO J 18(4):863–870. doi:10.1093/emboj/18.4.863

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Thyboll J, Kortesmaa J, Cao R, Soininen R, Wang L, Iivanainen A, Sorokin L, Risling M, Cao Y, Tryggvason K (2002) Deletion of the laminin alpha4 chain leads to impaired microvessel maturation. Mol Cell Biol 22(4):1194–1202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Udani M, Zen Q, Cottman M, Leonard N, Jefferson S, Daymont C, Truskey G, Telen MJ (1998) Basal cell adhesion molecule/lutheran protein. The receptor critical for sickle cell adhesion to laminin. J Clin Invest 101(11):2550–2558. doi:10.1172/JCI1204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Vahedi K, Kubis N, Boukobza M, Arnoult M, Massin P, Tournier-Lasserve E, Bousser MG (2007) COL4A1 mutation in a patient with sporadic, recurrent intracerebral hemorrhage. Stroke 38(5):1461–1464. doi:10.1161/STROKEAHA.106.475194

    Article  PubMed  Google Scholar 

  40. van der Flier A, Badu-Nkansah K, Whittaker CA, Crowley D, Bronson RT, Lacy-Hulbert A, Hynes RO (2010) Endothelial alpha5 and alphav integrins cooperate in remodeling of the vasculature during development. Development 137(14):2439–2449. doi:10.1242/dev.049551

    Article  PubMed  PubMed Central  Google Scholar 

  41. van der Knaap MS, Smit LM, Barkhof F, Pijnenburg YA, Zweegman S, Niessen HW, Imhof S, Heutink P (2006) Neonatal porencephaly and adult stroke related to mutations in collagen IV A1. Ann Neurol 59(3):504–511. doi:10.1002/ana.20715

    Article  PubMed  Google Scholar 

  42. Vestweber D (2015) How leukocytes cross the vascular endothelium. Nat Rev Immunol 15(11):692–704. doi:10.1038/nri3908

    Article  CAS  PubMed  Google Scholar 

  43. Wolburg H, Wolburg-Buchholz K, Kraus J, Rascher-Eggstein G, Liebner S, Hamm S, Duffner F, Grote EH, Risau W, Engelhardt B (2003) Localization of claudin-3 in tight junctions of the blood-brain barrier is selectively lost during experimental autoimmune encephalomyelitis and human glioblastoma multiforme. Acta Neuropathol 105(6):586–592. doi:10.1007/s00401-003-0688-z

    CAS  PubMed  Google Scholar 

  44. Wolburg-Buchholz K, Mack AF, Steiner E, Pfeiffer F, Engelhardt B, Wolburg H (2009) Loss of astrocyte polarity marks blood-brain barrier impairment during experimental autoimmune encephalomyelitis. Acta Neuropathol 118(2):219–233. doi:10.1007/s00401-009-0558-4

    Article  CAS  PubMed  Google Scholar 

  45. Wu C, Ivars F, Anderson P, Hallmann R, Vestweber D, Nilsson P, Robenek H, Tryggvason K, Song J, Korpos E, Loser K, Beissert S, Georges-Labouesse E, Sorokin LM (2009) Endothelial basement membrane laminin alpha5 selectively inhibits T lymphocyte extravasation into the brain. Nat Med 15(5):519–527. doi:10.1038/nm.1957

    Article  CAS  PubMed  Google Scholar 

  46. Yamamoto H, Ehling M, Kato K, Kanai K, van Lessen M, Frye M, Zeuschner D, Nakayama M, Vestweber D, Adams RH (2015) Integrin beta1 controls VE-cadherin localization and blood vessel stability. Nat Commun 6:6429. doi:10.1038/ncomms7429

    Article  CAS  PubMed  Google Scholar 

  47. Yao Y, Chen ZL, Norris EH, Strickland S (2014) Astrocytic laminin regulates pericyte differentiation and maintains blood brain barrier integrity. Nat Commun 5:3413. doi:10.1038/ncomms4413

    PubMed  PubMed Central  Google Scholar 

  48. Yousif LF, Di Russo J, Sorokin L (2013) Laminin isoforms in endothelial and perivascular basement membranes. Cell Adh Migr 7(1):101–110. doi:10.4161/cam.22680

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Physiological Chemistry and Pathobiochemistry, University of Muenster, 48149, Muenster, Germany

    Melanie-Jane Hannocks, Jula Huppert, Xueli Zhang, Eva Korpos & Lydia Sorokin

  2. Cells-In-Motion Cluster of Excellence, University of Muenster, 48149, Muenster, Germany

    Melanie-Jane Hannocks, Jula Huppert, Xueli Zhang, Eva Korpos & Lydia Sorokin

Authors
  1. Melanie-Jane Hannocks
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jula Huppert
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xueli Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eva Korpos
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lydia Sorokin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lydia Sorokin .

Editor information

Editors and Affiliations

  1. Theodor Kocher Institute, University of Bern, Bern, Switzerland

    Ruth Lyck

  2. Theodor Kocher Institute, University of Bern, Bern, Switzerland

    Gaby Enzmann

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Hannocks, MJ., Huppert, J., Zhang, X., Korpos, E., Sorokin, L. (2017). The Contribution of the Extracellular Matrix to the BBB in Steady State and Inflammatory Conditions. In: Lyck, R., Enzmann, G. (eds) The Blood Brain Barrier and Inflammation. Progress in Inflammation Research. Springer, Cham. https://doi.org/10.1007/978-3-319-45514-3_3

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-45514-3_3

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-45512-9

  • Online ISBN: 978-3-319-45514-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics