Leukocyte accumulation is a hallmark of inflammatory renal diseases. TNF, a potent cytokine that regulates leukocyte trafficking is essential for the development of glomerulonephritis in animal models. Many of the pro- inflammatory responses of TNF in vivo can be attributed to its effects on the vascular endothelium and leukocyte influx. TNF relays its biological activities by two distinct receptors, TNFR1 and TNFR2 with most of TNF's effects on the endothelium being attributed to TNFR1. The contribution of TNFR2 is likely underestimated as it has a higher affinity for the membrane bound versus the soluble form of the cytokine and it is not constitutively expressed in all endothelial cell cultures. Our recently published data demonstrate that engagement of TNFR2 in cultured endothelial cells triggers Interferon regulatory factor-1 (IRF-1) induced IFN? synthesis, and subsequent autocrine signaling via the IFN????receptor, to generate mononuclear cell chemoattractants. In vivo, acute renal inflammation induced by intravenously administered recombinant TNF results in neutrophil and monocyte recruitment in the kidney that requires TNFR1, while the TNFR2-IRF-1- IFN? autocrine loop is essential only for monocyte/macrophage accumulation. In a chronic model of anti- glomerular basement membrane nephritis, renal TNFR2 and IRF-1 but not TNFR1 are essential for sustained macrophage accumulation. Thus, our data identify a previously unrecognized TNFR2-IRF-1-IFN?-IFN????receptor-signaling pathway in endothelial cells that promotes monocyte recruitment. These findings may have relevance in humans as TNFR2, absent in normal human kidney, is robustly induced on the glomerular endothelium of patients with anti-GBM nephritis. Our results raise two important questions: How does TNFR2 induce IRF-1, and what steps of leukocyte recruitment in the kidney are regulated by TNFR2 and its associated IFN??autocrine loop? These questions will be addressed in three specific aims: I) Delineate TNFR2 proximal intracellular signals that link TNFR2 to IRF-1 and IFN??production;II) Conduct intravital microscopy in the intact kidney to elucidate pathways of renal leukocyte recruitment triggered by TNF;and III) Elucidate the molecular requirements for renal TNFR2 and components of the IFN? autocrine loop in the dynamics of monocyte recruitment.
For Aims II and III, we have developed a multiphoton intravital microscopy approach for time-lapse imaging of leukocyte behavior in the glomerular and peritubular capillaries of mice. Determining how TNF-induced amplification of IFN? expression and IFN?-signaling locally in the endothelium leads to monocyte accumulation in the kidney could result in important new insights into the pathogenesis of glomerulonephritis and lead to new therapeutic targets.
Glomerulonephritis, an inflammatory disease, is a leading cause of end stage renal disease worldwide. Renal macrophage accumulation is a hallmark of disease. It correlates with the degree of renal dysfunction and disease progression in patients and is responsible for renal injury in animal models of anti-GBM nephritis. This project will characterize how monocyte recruitment into the kidney is regulated by TNF, which may result in the identification of novel immunotherapeutic targets that prevent renal monocyte infiltration and associated organ injury.
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