TNFR2 induces IRF‐1 dependent IFNβ autocrine signaling in endothelial cells to promote monocyte recruitment

Abstract

Endothelial mechanisms of neutrophil recruitment are well studied but the signals that promote mononuclear cell influx remain unclear. We discovered that acute TNF stimulation of murine microvascular endothelial cells, which express TNFR1 and TNFR2 strongly induced mononuclear CXCR3 chemokines through Interferon regulatory factor‐1 (IRF‐1) induced IFNβ synthesis, and subsequent autocrine signaling via the IFNα/β‐receptor and STAT1. Both TNFR2 and TNFR1 were required for IRF‐1‐IFNβ signaling induced by soluble TNFα. A role for TNFR2 in the induction of IRF‐1, IFNβ and CXCR3 chemokines was confirmed following its overexpression and ligand independent activation in human endothelial cells. In vivo, acute renal inflammation induced by intravenously administered recombinant TNF resulted in neutrophil and monocyte recruitment in the kidney that required TNFR1, while the TNFR2‐IRF‐1‐IFNβ autocrine loop was essential only for monocyte/macrophage accumulation. In a chronic model of anti‐glomerular basement membrane nephritis, IRF‐1 and renal expressed TNFR2, but not TNFR1, were essential for sustained macrophage accumulation. Thus, our data identify a previously unrecognized signaling pathway in endothelial cells that is responsible for selectively recruiting monocytes during a TNF‐induced inflammatory response.This work was supported by the NIH PO1HL036028, RO1 DK51643 ( T.M.)