Dendritic cells (DCs) and macrophages are major components of the intrarenal immune system, but their contribution to disease progression in focal segmental glomerulosclerosis (FSGS ) is unclear. In this
research project, we will investigate this question in a newly developed model of this disease. We have already detected distinct immune cell infiltrates in this model and demonstrated strong activation of
proinflammatory signaling pathways at the transcriptional level.
We will first analyze the composition of immune cell infiltrates, and then clarify which chemokines act as attractants in the establishment of the infiltrate. Furthermore, we will visualize the dynamics of disease progression by light-sheet microscopy in optically clarified kidneys and correlate it with the infiltrate. Finally, we will use the newly established MCD/FSGS patient registry to identify diagnostic markers in immune cells in the blood and urine of FSGS patients.
Our project will not only provide a deeper understanding of immune cell function in the pathogenesis of FSGS, but also help personalize immunosuppressive strategies so that clinicians can select the optimal therapeutic strategy.
PROJECT RELATED PUBLICATIONS
Jobin K., Stumpf N.E., Schwab S., Eichler M., Neubert P., Rauh M., Adamowski M., Babyak O., Hinze D., Sivalingam S., Weisheit C., Hochheiser K., Schmidt S., Meissner M., Garbi N., Abdullah Z., Wenzel U., Hölzel M., Jantsch J., Kurts C. A high-salt diet compromises the neutrophil response against bacterial infections through hormonal perturbations. Science Transl Med, Epub Mar 25;12(536) (2020).
Brähler, S., Zinselmeyer B.H., Raju S., Nitschke M., Suleiman H., Saunders B.T., Johnson M.W., Böhner A.M.C., Viehmann S.F., Theisen D.J., Kretzer N.M., Briseño C.G., Zaitsev K., Ornatsky O., Chang Q., Carrero J.A., Kopp J.B., Artyomov M.N., Kurts C., Murphy K.M., Miner J.H. & Shaw A.S. Opposing Roles of Dendritic Cell Subsets in Experimental GN. J. Am. Soc. Nephrol. 29, 138–154 (2018).
Brähler, S. Yu H., Suleiman H., Krishnan G.M., Saunders B.T., Kopp J.B., Miner J.H., Zinselmeyer B.H. & Shaw A.S. Intravital and Kidney Slice Imaging of Podocyte Membrane Dynamics. J. Am. Soc. Nephrol. 27, 3285–3290 (2016).
Yu H., Artomov M., Brähler S., Stander M.C., Shamsan G., Sampson M.G., White J.M., Kretzler M., Miner J.H., Jain S., Winkler C.A., Mitra R.D. Kopp J.B., Daly M.J., Shaw A.S. A role for genetic susceptibility in sporadic focal segmental glomerulosclerosis. J Clin Invest. 126(4):1603 (2016).
Ludwig-Portugall I., Bartok E., Dhana E., Evers B.D.G., Primiano M.J., Hall P.J., Franklin B.S., Hornung V., Hartmann G., Boor P., Latz E., Kurts C. A NLRP3-specific inflammasome inhibitor potently attenuates crystal-induced kidney fibrosis in vivo. Kidney Int, 90:525-39 (2016).
Schiwon M., Weisheit C., Franken L., Gutweiler S., Dixit A., Meyer-Schwesinger C., Pohl J., Maurice N.J., Thiebes S., Lorenz K., Quast T., Fuhrmann M., Baumgarten G., Lohse M.J., Opdenakker G., Bernhagen J., Bucala R., Panzer U., Kolanus W., Gröne H.J., Garbi N., Kastenmüller W., Knolle P.A., Kurts C, Engel DR. Crosstalk between sentinel and helper macrophages permits neutrophil migration into infected uroepithelium. Cell 156:456–68 (2014).
Hochheiser K., Heuser C., Krause T.A., Teteris S., Ilias A., Weisheit C., Hoss F., Tittel A.P., Panzer U., Knolle P.A., Engel D.R., Tharaux P.L., Kurts C. Exclusive CX3CR1-dependence of kidney cortical dendritic cells impacts glomerulonephritis progression. J Clin Invest, 123(10):4242-54 (2013).
Tittel A.P., Heuser C., Ohliger C., Yona S., Hämmerling G.J., Engel D.R., Garbi N., Kurts C. Functionally relevant neutrophilia in CD11c-diphteria toxin receptor transgenic mice. Nat Methods 9(4):385-90 (2012).
Brähler, S., Ising C., Hagmann H., Rasmus M., Hoehne M., Kurschat C., Kisner T., Goebel H., Shankland S., Addicks K., Thaiss F., Schermer B., Pasparakis M., Benzing T. & Brinkkoetter PT. Intrinsic proinflammatory signaling in podocytes contributes to podocyte damage and prolonged proteinuria. Am J Physiol Renal Physiol 303(10):F1473- 85 (2012).
