The role of GTPases in integrin activation and leukocyte recruitment

    Leukocyte recruitment into inflamed tissue is tightly regulated. GTPases in leukocytes are involved in leukocyte recruitment, but the role of regulators of GTPases is still unknown. Here, we will investigate different molecules involved in the regulation of Rac activity which is involved in leukocyte recruitment. Furthermore, we will investigate how myosin 9B, a RhoA specific GAP, participates in integrin activation and leukocyte recruitment. We will use gene-deficient mice, retrovirus technology, and biochemical methods to the molecular mechanisms of integrin activation and leukocyte recruitment in vitro and in vivo.

    Research area: Leukocyte biology

    Prof. Dr. med. Alexander Zarbock

    Funding period: July 2012 - June 2020

    • Publications

      Original articles

      • Herter JM, Margraf A, Volmering S, Correia BE, Bradshaw JM, Bisconte A, Hill RJ, Langrish CL, Lowell CA, Zarbock A. PRN473, an inhibitor of Bruton's tyrosine kinase, inhibits neutrophil recruitment via inhibition of macrophage antigen?1 signalling. Br J Pharmacol. 2018;175(3):429-439. 
      • Boras M, Volmering S, Bokemeyer A, Rossaint J, Block H, Bardel B, Van Marck V, Heitplatz B, Kliche S, Reinhold A, Lowell C, Zarbock A. (2017) Skap2 is required for β2 integrin-mediated neutrophil recruitment and functions. J Exp Med. 214(3):851-874. (doi: 10.1084/jem.20160647) [Epub 2017 Feb 9]
      • Volmering S, Block H, Boras M, Lowell C, Zarbock A (2016) The neutrophil Btk signalosome regulates multiple Mac-1 integrin activation events involved in neutrophil recruitment and functions during sterile inflammation. Immunity. 19;44(1):73-87.
      • Block H, Stadtmann A, Riad D, Rossaint J, Sohlbach C, Germena G, Wu D, Simon SI, Ley K, Zarbock A. (2015) Gnb isoforms orchestrate a signaling pathway comprising Rac1 and Plcβ2/3 leading to LFA-1 activation and neutrophil arrest in vivo. Blood 2015 Oct 14. pii: blood-2015-06-651034
      • Drechsler M, de Jong R, Rossaint J, Viola JR, Leoni G, Wang JM, Grommes J, Hinkel R, Kupatt C, Weber C, Döring Y, Zarbock A, Soehnlein O. (2015) Annexin A1 counteracts chemokine-induced arterial myeloid cell recruitment. Circ Res. 2015 Feb 27;116(5):827-35. AZ und OS contributed equally and share senior-authorship
      • Germena G, Volmering S, Sohlbach C, Zarbock A. Mutation in the CD45 inhibitory wedge modulates integrin activation and leukocyte recruitment during inflammation. J Immunol. 2015,15;194:728.
      • Stadtmann A, Block H, Volmering S, Abram C, Sohlbach C, Boras M, Lowell CA, Zarbock A. (2015) Cross-Talk between Shp1 and PIPKIγ Controls Leukocyte Recruitment. J Immunol. 2015 Aug 1;195(3):1152-61.
      • Sreeramkumar V, Adrover JM, Ballesteros I, Cuartero MI, Rossaint J, Bilbao I, Nácher M, Pitaval C, Radovanovic I, Fukui Y, McEver RP, Filippi MD, Lizasoain I, Ruiz-Cabello J,Zarbock A, Moro MA, Hidalgo A (2014) Neutrophils scan for activated platelets to initiate inflammation. Science 346(6214): 1234-1238.
      • Poeter M, Brandherm I, Rossaint J, Rosso G, Shahin V, Skryabin BV, Zarbock A, Gerke V, Rescher U (2014) Annexin A8 controls leukocyte recruitment to activated endothelial cells via cell surface delivery of CD63. Nat Commun 5: 3738. [doi: 10.1038/ncomms4738.]
      • Schneider-Hohendorf T, Rossaint J, Mohan H, Böning D, Breuer J, Kuhlmann T, Gross CC, Flanagan K, Sorokin L, Vestweber D, Zarbock A, Schwab N, Wiendl H (2014) VLA-4 blockade promotes differential routes into human CNS involving PSGL-1 rolling of T cells and MCAM-adhesion of TH17 cells. J Exp Med 211 (9): 1833-1846.  (doi: 10.1084/jem.20140540)
      • Herter JM, Rossaint J, Spieker T, Zarbock A (2014) Adhesion molecules involved in neutrophil recruitment during sepsis-induced acute kidney injury. J Innate Immun, 6(5): 597-606. [doi: 10.1159/000358238. Epub 2014 Feb 25.].
      • Herter JM, Rossaint J, Block H, Welch H, Zarbock A (2013) Integrin activation by P-Rex1 is required for selectin-mediated slow leukocyte rolling and intravascular crawling. Blood 121(12): 2301-2310.
      • Rossaint J, Berger C, Van Aken H, Scheld HH, Zahn PK, Rukosujew A, Zarbock A (2012) Cardiopulmonary bypass during cardiac surgery modulates systemic inflammation by affecting different steps of the leukocyte recruitment cascade. PLoS One 7(9): e45738.