STAT1 and IRF8 in Vascular Inflammation and Cardiovascular Disease: Diagnostic and Therapeutic Potential

Abstract

Inflammation importantly contributes to the pathophysiology of Cardiovascular Disease (CVD). Signal Transducer and Activator of Transcription (STAT)1 operates at the frontier of innate and adaptive immunity and its involvement in CVD has been widely appreciated. A unique role of STAT1 in cross-talk between the pro-inflammatory cytokine IFNγ and TLR4 activators (TLR4-A) has been uncovered in immune as well as vascular cells increasing inflammation. Interferon Regulatory Factor (IRF)8 whose expression was initially identified in immune cells, controls development and differentiation in close connection with PU.1. In addition, as a STAT1-target, IRF8 accounts for "immune cell-specific" STAT1-dependent functions of IFNγ and LPS. Novel studies prove that also in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), STAT1 and IRF8 orchestrate a transcriptional platform for cross-talk between IFNγ and TLR4-A, which leads to amplified pro-atherogenic responses in the vasculature. In addition to its known immune cell functions, this points to a novel "inflammation-dependent" role of IRF8 in vascular cells. In this review we present a summary of these findings and postulate STAT1- and IRF8-target genes as promising markers of vascular inflammation, and STAT1 and IRF8 as potential targets for the development of new immunosuppressive and anti-inflammatory agents for the treatment of CVD.

Mechanisms of the Innate Defense Regulator Peptide-1002 Anti-Inflammatory Activity in a Sterile Inflammation Mouse Model

“…For example, Irf8 participates in the transcriptional regulation of TLR4 signaling in murine lung during endotoxemia (56). Irf8 and Stat1 have been shown to mediate the cross-talk between LPS-induced TLR4 signaling and the IFN-g response; both are key processes contributing to the early stages of atherosclerosis and plaque development (48). Furthermore, Irf8-regulated Ccl5, Isg15, Cd274, Oasl2, Slc15a3, and Gbp2 expression was previously found to drive the pathological inflammation during cerebral malaria (80).…”

“…Irf8 is a transcription factor that is restricted primarily to hematopoietic cells and often acts by associating with other transcription factors to modulate key inflammatory responses, including the IFN-g response, TLR signaling, and the expression of inducible NO synthase (48,49). When comparing PMA and IDR-1002 combined treatment with PMA challenge, Irf8 was identified to be one of the central hubs in the zero-order protein-protein interaction network, interacting with 28 other transcriptionally dysregulated proteins (27 of which were upregulated by PMA and suppressed in the presence of IDR-1002 treatment) ( Fig.…”

“…Irf8 and Irf1 are also involved in IFN-g-induced TNF-a expression (57). Furthermore, Irf8 participates in the transcriptional regulation of the LPS-induced TLR4 cascade and the crosstalk between TLR4 signaling and the IFN-g response (48,56). Because Irf8 plays a critical role in upregulating inflammation in cooperation with various transcription factors, we propose that IDR-1002 acts to control a variety of inflammatory responses by suppressing the induction of Irf8 and its target genes, such as Ccl5, TNF, and TLR4.…”

San-Huang-Xie-Xin-Tang Constituents Exert Drug-Drug Interaction of Mutual Reinforcement at Both Pharmacodynamics and Pharmacokinetic Level: A Review

“…It has been reported that STAT1 and STAT5, the downstream molecules of IFN-γ, are also likely to be implicated in inflammation (Chmielewski et al, 2015; Li X. et al, 2015). Akt functions as emerging crucial regulator of multiple cellular processes, such as apoptosis, differentiation, survival, etc., (Piao et al, 2015).…”

Dysregulated expression of STAT1, miR‐150, and miR‐223 in peripheral blood mononuclear cells of coronary artery disease patients with significant or insignificant stenosis

“…Understanding the disruption of molecular mechanisms responsible for regulating these inflammatory processes may provide useful insights into CAD pathogenesis. The JAK/STAT signaling is among the most important regulatory pathways governing several inflammatory processes through the initiation of innate and adaptive immunity and mediation of divers cytokine signaling pathways . STAT1 is a member of STAT transcription factors family which transduce cytokine signaling to the nucleus following tyrosine phosphorylation/activation by JAK proteins and it is believed to be relevant to the pathogenesis of cardiovascular diseases .…”