2 | Effects of endothelial basement membrane on monocyte/macrophage differentiation and heterogeneity

Recent data indicates that monocyte interactions with endothelial cells promote monocyte differentiation towards macrophages. In addition, macrophages have been recently shown to be a highly heterogeneous population with different functions at different sites. Using high-resolution imaging and markers of the endothelial and parenchymal basement membranes together with endothelial and astroglial markers, we will precisely localise different macrophages in relation to the endothelium and underlying basement membranes, and will address the question of whether extracellular matrix is involved in their retention at defined sites and/or their differentiation towards different macrophage populations. Unique transgenic mouse lines lacking basement membrane laminins (Lama4-/-, Tie2Lama5-/-) and macrophage reporter mice will be employed, together with in vitro adhesion, migration and differentiation assays.

Publications

  • Gerwien H, Hermann S, Zhang X, Korpos E, Song J, Kopka K, Faust A, Wenning C, Gross C C,Honold L, Melzer N, Opdenakker G, Wiendl H, Schäfers M, Sorokin L. Imaging matrix metalloproteinase activity in multiple sclerosis as a specific marker of leukocyte penetration of the blood-brain barrier. Sci Transl Med; 2016;8:364ra152
  • Song J, Wu C, Korpos E, Zhang X, Agrawal SM, Wang Y, Faber C, Schäfers M, Körner H, Opdenakker G, Hallmann R, Sorokin L. Focal MMP-2 and MMP-9 activity at the blood-brain barrier promotes chemokine-induced leukocyte migration. Cell Rep 2015;10:1040-1054.
  • Enzmann G, Mysiorek C, Gorina Y-J, Cheng R, Ghavampour S, Hannocks M-J, Prinz V, Dirnagl U, Endres M, Prinz M, Beschorner R, Harter R, Mittelbronn M, Engelhardt B, Sorokin L. The neurovascular unit as a selective barrier to polymorphonuclear granulocyte (PMN) infiltration into the brain after ischemic injury. Acta Neuropathologica 2013;125: 395-412.
  • Sorokin, L. The impact of the extracellular matrix on inflammation. Nat Rev Immunol 2010; 10:712-723.
    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. Endothelial basement membrane laminin alpha5 selectively
  • inhibits T lymphocyte extravasation into the brain. Nature Medicine, 2009;15:519-527.
  • Agrawal S, Anderson P, Durbeej M, van Rooijen N, Ivars F, Opdenakker G, Sorokin LM. Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis. J Exp Med 2006;203:1007-1019.

Potential secondments

UKLFR (Marco Prinz) month 6-8, UNIBS (Marina Pizzi) month 18-20; MIM (Paul Vulto) month 28-30

Host Organisation:
Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Germany
Supervisor:
Lydia Sorokin