Molecular mechanisms of uremia-associated modulation of inflammation in chronic kidney disease.
Final Report Abstract
Leukocyte recruitment to the site of inflammation plays a pivotal role in host defence. Previous studies and clinical evidence indicate a disturbance of leukocyte recruitment and activation alongside persistently reduced kidney function during CKD. We could show that CKD impairs leukocyte recruitment to sites of inflammation, which was associated with reduced bacterial clearance during bacterial pneumonia. Furthermore, we could also demonstrate that CKD impairs cell-intrinsic leukocyte functions, for example ROS production. Mechanistically, we could show that FGF23 accumulates during CKD and that elevated FGF23 levels inhibit neutrophil recruitment and activation. This effect of FGF23 is mediated by binding to its receptor FGFR2 expressed on leukocytes. FGF23 binding to FGFR2 activates an inhibitory intracellular signalling cascade including proteinkinase A (PKA), which attenuates chemokine-induced activation of ß2 integrins. Further insights into how the inhibition of integrin activation during CKD is mechanistically regulated may offer new therapeutic approaches to treat recurrent infections in CKD patients and warrants further studies in the future.
Publications
- FGF23 signaling impairs neutrophil recruitment and host defense during CKD. J Clin Invest. 2016 Mar 1;126(3):962-74
Rossaint J, Oehmichen J, Van Aken H, Reuter S, Pavenstädt HJ, Meersch M, Unruh M, Zarbock A
(See online at https://doi.org/10.1172/JCI83470) - Fibroblast growth factor 23 actions in inflammation: a key factor in CKD outcomes. Nephrol Dial Transplant. 2017 Sep 1;32(9):1448-1453
Rossaint J, Unruh M, Zarbock A
(See online at https://doi.org/10.1093/ndt/gfw331)
