The role of intracellular calcium regulators in integrin activation and leukocyte recruitment

    During infections, leukocytes are rapidly recruited into inflamed tissues in a coordinated sequence of events that is needed for an adequate immune response. STIM calcium sensing proteins and ORAI-calcium channels are involved in store-operated calcium entry (SOCE) regulation in immune cells. Preliminary data indicate that STIM1 and ORAI1 are required for chemokine-induced integrin activation and neutrophil arrest. Here, we will address the following questions: 1) What is the interconnection between calcium-concentration regulating proteins and GTPases in neutrophils? 2) Which role do STIM and ORAI play during the regulation of integrin activity and 3) for the different steps of neutrophil recruitment?

    Research area: Leukocyte biology

    Prof. Dr. med. Alexander Zarbock

    Funding period: July 2012 - June 2024

    • Publications

      Original articles

      • Lindemann O, Rossaint J, Najder K, Schimmelpfennig S, Hofschröer V, Wälte M, Fels B, Oberleithner H, Zarbock A, Schwab A (2020) Intravascular adhesion and recruitment of neutrophils in response to CXCL1 depends on their TRPC6 channels. J Mol Med (Berl) 98(3):349-360
      • Margraf A, Germena G, Drexler HCA, Rossaint J, Ludwig N, Prystaj B, Mersmann S, Thomas K, Block H, Gottschlich W, Liu C, Krenn PW, Haller H, Heitplatz B, Meyer Zu Brickwedde M, Moser M, Vestweber D, Zarbock A (2020) The integrin-linked kinase is required for chemokine-triggered high-affinity conformation of the neutrophil β2-integrin LFA-1. Blood 5;136(19):2200-2205
      • Margraf A, Cappenberg A, Vadillo E, Ludwig N, Thomas K, Körner K, Zondler L, Rossaint J, Germena G, Hirsch E, Zarbock A (2020) ArhGAP15, a RacGAP, Acts as a Temporal Signaling Regulator of Mac-1 Affinity in Sterile Inflammation.1;205(5):1365-1375
      • 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.