Endothelial TNF Receptor 2 Induces IRF1 Transcription Factor-Dependent Interferon-β Autocrine Signaling to Promote Monocyte Recruitment

• Published in: Immunity (Cambridge, Mass.) Mass.), 2013-05, Vol.38 (5), p.1025-1037
• Main Authors: Venkatesh, Deepak, Ernandez, Thomas, Rosetti, Florencia, Batal, Ibrahim, Cullere, Xavier, Luscinskas, Francis W., Zhang, Yuzhi, Stavrakis, George, García-Cardeña, Guillermo, Horwitz, Bruce H., Mayadas, Tanya N.
• Format: Article
• Language: English
• Subjects: Animals; Autocrine Communication - immunology; Cells, Cultured; Endothelial Cells - metabolism; Humans; Inflammation - immunology; Interferon Regulatory Factor-1 - genetics; Interferon Regulatory Factor-1 - metabolism; Interferon-beta - metabolism; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes - immunology; Monocytes - metabolism; Nephritis - metabolism; Neutrophils - metabolism; Receptor, Interferon alpha-beta - metabolism; Receptors, CXCR3 - biosynthesis; Receptors, Tumor Necrosis Factor, Type I - biosynthesis; Receptors, Tumor Necrosis Factor, Type II - biosynthesis; Receptors, Tumor Necrosis Factor, Type II - metabolism; STAT1 Transcription Factor - metabolism; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2013.01.012

Endothelial-dependent mechanisms of mononuclear cell influx are not well understood. We showed that acute stimulation of murine microvascular endothelial cells expressing the tumor necrosis factor receptors TNFR1 and TNFR2 with the soluble cytokine TNF led to CXCR3 chemokine generation. The TNF receptors signaled through interferon regulatory factor-1 (IRF1) to induce interferon-β (IFN-β) and subsequent autocrine signaling via the type I IFN receptor and the transcription factor STAT1. Both TNFR2 and TNFR1 were required for IRF1-IFNβ signaling and, in human endothelial cells TNFR2 expression alone induced IFN-β signaling and monocyte recruitment. In vivo, TNFR1 was required for acute renal neutrophil and monocyte influx after systemic TNF treatment, whereas the TNFR2-IRF1-IFN-β autocrine loop was essential only for macrophage accumulation. In a chronic model of proliferative nephritis, IRF1 and renal-expressed TNFR2 were essential for sustained macrophage accumulation. Thus, our data identify a pathway in endothelial cells that selectively recruits monocytes during a TNF-induced inflammatory response. [Display omitted] •TNF-α triggers an endothelial IFN-β autocrine loop leading to mononuclear chemokines•Endothelial TNFR2 and TNFR1 are required for IRF1 and IFN-β autocrine signaling•Activation of TNFR2 alone can promote IFN-β generation and monocyte recruitment•The TNFR2-IRF1-IFN-β loop promotes renal monocyte recruitment in vivo