Research Report 2010 - MDC

Associated scientists and clinical scientistsProf. Friedrich C. LuftManager of sponsored programsSusanne WisslerTechnical AssistantsSusanne RolleSylvia Krügerthat were exposed to 40° C for 1 hour showed stronglyreduced GM-CSF- and IL-8-induced neutrophilic skininflammation. In vitro heat exposure abrogated migrationtoward both cytokines by down-regulating PI3-K/Akt. Furthermore, neutrophils on fibronectin showedabrogated NF-κB activation in response to GM-CSF andIL-8 after heat. Less NF-κB activation was seen in theinflammatory lesions of mice exposed to fever-like temperaturesas demonstrated by in situ hybridization forIκBα mRNA. These new findings suggest that heat mayhave anti-inflammatory effects in neutrophil-dependentinflammation. Thus, we believe we should let feversbe!ANCA from a patient with active vasculitis shows a cytoplasmicimmunofluorescence staining pattern in permeabilized neutrophils(left). Necrotizing crescentic glomerulonephritis in a mouse model ofANCA vasculitis (right).Is platelet dust more important than stardust?Birgit Salanova and the group tested the notion thatplatelets could “spill over” functional glycoproteinIIb/IIIa (GPIIb/IIIa) receptors onto neutrophils viaplatelet-derived microparticles (PMPs). The groupobserved that acquired GPIIb/IIIa receptors co-localizedwith beta2-integrins and cooperated in NF-κB activation.They showed that Src and Syk non-receptor tyrosinekinases, as well as the actin cytoskeleton, controlNF-kappaB activation. When granulocyte macrophagecolony-stimulating factor-treated neutrophils wereincubated on fibronectin, strong NF-κB activation wasobserved, but only after loading with PMPs. Currentlyavailable GPIIb/IIIa inhibitors were effective. The dataimplicate GPIIb/IIIa receptors as new therapeutic targetsin neutrophil-induced inflammation.BK channels and neutrophil functionThe group (in collaboration with Maik Gollasch (ECRC)and William Nauseef (University of Iowa) was involvedin an “intensive” controversy with a group at UniversityCollege London, regarding the importance of BK channelsin neutrophil “burst” reactions. To test this notion,Kirill Essin and the group directly assessed the role of BKchannels in neutrophil function, including the NADPHoxidase. Neutrophils lacking BK channels (BK-/-) hadnormal NADPH oxidase activity in response to receptorindependentand phagocytic challenges. Furthermore,NADPH oxidase activity of neutrophils and macrophageswas normal after treatment with BK channelinhibitors. The group concluded that the BK channel isnot required for NADPH oxidase activity in neutrophils.The contentious argument has been dropped.Selected PublicationsSchreiber, A, Xiao, H, Jennette, JC, Schneider, W, Luft, FC, Kettritz, R. (2009)C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis.J Am Soc Nephrol. 20, 289-298.Choi, M, Salanova, B, Rolle, S, Wellner, M, Schneider, W, Luft, FC, Kettritz, R.(2008) Short-term heat exposure inhibits inflammation by abrogatingrecruitment of and nuclear factor-{kappa}B activation in neutrophilsexposed to chemotactic cytokines. Am J Pathol. 172, 367-777.von Vietinghoff, S, Choi, M, Rolle, S, Luft, FC, Kettritz, R. (2007) Febrile temperaturescontrol antineutrophil cytoplasmic autoantibody-induced neutrophilactivation via inhibition of phosphatidylinositol 3-kinase/Akt.Arthritis Rheum. 56, 3149-3158.Salanova, B, Choi, M, Rolle, S, Wellner, M, Luft, FC, Kettritz, R. (2007) Beta2-integrins and acquired glycoprotein IIb/IIIa (GPIIb/IIIa) receptors cooperatein NF-kappaB activation of human neutrophils. J Biol Chem. 282,27960-27969.Essin, K, Gollasch, M, Rolle, S, Weissgerber, P, Sausbier, M, Bohn, E,Autenrieth, IB, Ruth P, Luft, FC, Nauseef,WM, Kettritz, R.(2009) BK channelsin innate immune functions of neutrophils and macrophages. Blood 113,1326-1331.The Experimental and Clinical Research Center 211