Inflammation and an influx of macrophages are common elements in many diseases. Among pro-inflammatory cytokines, tumor necrosis factor α (TNFα) plays a central role by amplifying the cytokine network. Progranulin (PGRN) is a growth factor that binds to TNF receptors and interferes with TNFα-mediated signaling. Extracellular PGRN is processed into granulins by proteases released from immune cells. PGRN exerts anti-inflammatory effects, whereas granulins are pro-inflammatory. The factors coordinating these ambivalent functions remain unclear. In our study, we identify Y-box binding protein-1 (YB-1) as a candidate for this immune-modulating activity. Using a yeast-2-hybrid assay with YB-1 protein as bait, clones encoding for progranulin were selected using stringent criteria for strong interaction. We demonstrate that at physiological concentrations, YB-1 interferes with the binding of TNFα to its receptors in a dose-dependent manner using a flow cytometry-based binding assay. We show that YB-1 in combination with progranulin interferes with TNFα-mediated signaling, supporting the functionality with an NF-κB luciferase reporter assay. Together, we show that YB-1 displays immunomodulating functions by affecting the binding of TNFα to its receptors and influencing TNFα-mediated signaling via its interaction with progranulin.
The deposition of immune complexes is the causal factor in distinct renal pathologies, e.g., lupus nephritis and membranous nephritis. The location of these deposits within a tissue biopsy is often the key to establishing a diagnosis. However, how immune complexes come to be deposited below the vascular endothelium was, until now, a mystery, as was their contribution to inducing inflammation. A recent paper in Cell by Stamatiades et al. (Cell 164(4):991-1003, 2016) demonstrates the active transport of immune complexes by the vascular endothelial cells and an Fc receptor-dependent uptake by tissue-resident macrophages. This leads to the activation of these macrophages and the release of pro-inflammatory cytokines, which in turn recruits immune cells from the blood into the kidney. The identification of these mechanisms should lead to a better stratification of kidney diseases and hopefully to the development of specific therapies.
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