Cross‐talk between STAT1 and PI3K/AKT signaling in HIV‐1‐induced blood–brain barrier dysfunction: Role of CCR5 and implications for viral neuropathogenesis

Abstract

How neuroinflammation affects signaling pathways leading to human blood–brain barrier (BBB) dysfunction during HIV-1 infection is incompletely understood. We previously demonstrated that signal transducers and activators of transcription-1 (STAT1) signaling is involved in HIV-1 induced BBB damage and is relevant to viral neuropathogenesis. The objective of this study was to delineate the signaling pathways upstream and downstream of STAT1 involved in HIV-1-induced endothelial dysfunction. We show that HIV-1 activation of STAT1 and STAT3 in human brain microvascular endothelial cells (HBMEC) is associated with induction of promoter activity of the interferon-stimulated response element (ISRE)/interferon-γ-activated sequence (GAS). The STAT1 inhibitor fludarabine diminished HIV-1-induced ISRE/GAS promoter activity. CCR5 neutralizing antibodies and the phosphoinositide-3-kinase (PI3K) inhibitor LY-294002 diminished HIV-1-induced phosphorylation of STAT1 and STAT3, significantly diminished HIV-1-induced ISRE/GAS promoter activity, and diminished virus-induced monocyte adhesion and transendothelial migration. HIV-1 infection did not phosphorylate janus kinases but induced activation of the phosphoinositide-dependent kinase-1 (PDK1) and the serine-threonine protein kinase AKT, both downstream effectors of PI3K. CCR5 antibodies also diminished virus-induced phosphorylation of PDK1 and AKT. These results suggest that the chemokine receptor CCR5 is partially involved in HIV-1 binding to HBMEC and show cross-talk between STAT1 and PI3K pathways in HIV-1-induced BBB dysfunction.

TGFβ1 exacerbates blood–brain barrier permeability in a mouse model of hepatic encephalopathy via upregulation of MMP9 and downregulation of claudin-5

“…One downstream consequence of TGFβ1 is the activation of phosphatidylinositol-3 kinase/Akt pathway signaling(42), which has been demonstrated to promote vascular permeability in cancer models(43, 44). Also, this pathway has been shown to induce BBB permeability following focal cerebral ischemia(45), HIV-induced BBB disruption(46), and traumatic brain injury(47). In addition to this, we have previously identified that inhibition of TGFβ1 can lead to increased expression of the hedgehog transcription factor Gli1(16).…”

STAT3 Regulates MMP3 in Heme-Induced Endothelial Cell Apoptosis

“…Microglial- mediated cell death also appears to involve JAK/STAT3 and NF-κB [62]. In addition, JAK/STAT signaling has been shown to promote and modulate inflammatory processes [62], [63] leading to human BBB dysfunction in HIV infection [64], the latter dysfunction was mediated through CCR5 receptor which is involved in HIV-1 binding to HBVEC and activating the phosphoinositide-dependent kinase-1 (PDK1) and the serine-threonine protein kinase AKT [64]. Furthermore, some studies have shown that JAK2-STAT3 activation plays a role in post-ischemic brain neuronal damage [54] and liver cell inflammation and apoptosis [65], [66].…”

Critical roles of chemokine receptor CCR5 in regulating glioblastoma proliferation and invasion

“…Intracellular signaling by chemokine receptors is dependent on neighboring G-proteins. Several signaling molecules related to the activation of chemokine receptors have been identified, including Akt/PKB, ERK1/2, mitogen-activated protein kinase, PI3K, STAT1, and NF-κB [20,29,50]. However, little is known about the downstream signaling pathways regulated by CCL5-CCR5 interaction in glioma.…”