STAT1 signaling modulates HIV-1–induced inflammatory responses and leukocyte transmigration across the blood-brain barrier

Abstract

The relationship among neuroinflammation, blood-brain barrier (BBB) dysfunction, and progressive HIV-1 infection as they affect the onset and development of neuroAIDS is incompletely understood. IntroductionHuman immunodeficiency virus type 1 (HIV-1) infection of the central nervous system (CNS) commonly results in behavioral, motor, and cognitive impairments. [1][2][3] Although disease severity and progression has slowed, in part, as a result of antiretroviral therapy, 76% to 83% of brain autopsies continue to show observable neuropathological abnormalities. [4][5][6] Disease pathology ranges from mild brain atrophy and gliosis to robust viral replication, multinucleated giant cell formation, astrogliosis and microgliosis, myelin pallor, and neuronal loss. 7,8 These pathological findings are collectively termed HIV-1 encephalitis (HIVE). HIVE is a common correlate to the later stages of behavioral, motor, neuropsychiatric, and neurologic consequences of disease termed HIV-1-associated dementia (HAD) (for recent reviews, see McArthur 1 ; Grant et al 2 ; Ghafouri 3 ). HIVE is fueled by viral infection and immune activation of brain mononuclear phagocytes (MPs: blood-derived perivascular macrophages and microglia). 9 Such MP-and virus-associated neuroinflammation promotes monocyte trafficking across the bloodbrain barrier (BBB), MP infiltration into the CNS, and neurodegeneration. [10][11][12] Thus, dysfunction of the BBB is one critical feature of HIV-1 neuropathogenesis.Brain microvascular endothelial cells, a major component of BBB function and integrity, are connected by tight junctions (TJs) that limit paracellular flux and restrict permeability. 13 Indeed, under normal physiologic conditions, the brain endothelium functions as an interface between the blood and the brain parenchyma, strictly regulating influx of ions, molecules, and leukocytes into the CNS. Nonetheless, in disease, a variety of environmental, toxic, degenerative, and microbial insults could cause BBB breakdown. 12,14 Such a breakdown occurs during progressive HIV-1 infection 12,[15][16][17] and was documented in laboratory, animal models, human clinical observations, and autopsy studies. 10,[16][17][18][19][20] Underlying mechanisms of BBB dysfunction and how it affects ongoing disease are incompletely understood. 1,12,14 Dysfunction of the BBB enhances penetration of cell-free virus, ingress of activated HIV-1-infected monocytes across the BBB, accumulation of MP in the CNS, and spread of the virus to neighboring microglia and astrocytes. 15,21 Thus, BBB breech is commonly associated with accelerated disease and the development of behavioral and cognitive deficits that are signatures of HAD. 1,16 Based on these observations, the elucidation of the signaling pathways mediating BBB compromise can prove important for understanding disease mechanisms and development of new therapies.Signal transducers and activators of transcription (STATs) proteins are latent cytoplasmic transcription factors that are phosphorylated by Janus kinases (JAKs) in...

Mononuclear phagocyte intercellular crosstalk facilitates transmission of cell-targeted nanoformulated antiretroviral drugs to human brain endothelial cells

“…Brain endothelial cell culture and cytotoxicity assays Primary HBMEC were isolated from brain tissue obtained during surgical removal of epileptogenic cerebral cortex in adult patients as described previously 24,25 and provided by Dr Marlys Witte and Dr Michael Bernas (University of Arizona, Tuscon, AZ). These brain tissues were collected under institutional review board-approved protocol at the University of Arizona.…”

“…Routine evaluation for von Willebrand factor, Ulex europeus lectin, and CD31 (all from Abcam, Cambridge, MA) demonstrated that cells were .99% pure. Freshly isolated cells were cultured as we previously described, 24,25 and cells at passage 2-4 were used in this study. To determine any potential toxic effects of nanoART on HBMEC, confluent cells were treated with nanoART at 0.1 mM to 0.27 mM for 2 hours at 37°C, 5% CO 2 .…”

Interleukin-6 primarily produced by non-hematopoietic cells mediates the lipopolysaccharide-induced febrile response

“…It has previously been reported that blood-borne IL-6 was able to alter the brain function by crossing the blood-brain barrier (Banks et al, 1994), which supports the idea that IL-6 in CSF, at least to some portion, may be derived from the periphery. Furthermore, it was suggested that circulating IL-6 was able to increase the vascular permeability of blood vessels in the blood-brain barrier (Paul et al, 2003) and to activate signal transducers and activators of transcription (STAT) 1 and 3 (Rummel et al, 2006), which have been described to be implicated in the damage of blood-brain barrier (Chaudhuri et al, 2008). However, with the current experimental approach we were not able to distinguish centrally produced IL-6 from IL-6 in the periphery, an issue that requires further examination.…”

Dysregulation of Claudin-5 in HIV-induced Interstitial Pneumonitis and Lung Vascular Injury. Protective Role of Peroxisome Proliferator–activated Receptor-γ

“…Monocytes, PBMC, and peripheral blood lymphocytes (PBL) were obtained by countercurrent centrifugal elutriation of leukopheresis packs from HIV-1, HIV-2, and hepatitis B-seronegative donors, and monocyte-derived macrophages (MDM) obtained as previously described (23). Cell culture, HIV-1 infection, and experiments assessing the effect of PPAR-g on viral infection were performed as detailed in the online supplement.…”

“…Protein extraction from cells and lung tissues, Western blot analyses, and microscopy were performed as previously described (23) and as detailed in the online supplement.…”